umu.sePublications
Change search
Link to record
Permanent link

Direct link
BETA
Gharibyan, Anna
Alternative names
Publications (10 of 17) Show all publications
Islam, T., Gharibyan, A. L., Golchin, S. A., Pettersson, N., Brännström, K., Hedberg, I., . . . Olofsson, A. (2019). Apolipoprotein E impairs amyloid-β fibril elongation and maturation. The FEBS Journal
Open this publication in new window or tab >>Apolipoprotein E impairs amyloid-β fibril elongation and maturation
Show others...
2019 (English)In: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658Article in journal (Refereed) Epub ahead of print
Abstract [en]

Alzheimer's disease (AD) is strongly linked to amyloid depositions of the Aβ peptide (Aβ). The lipid-binding protein apolipoprotein E (ApoE) has been found to interfere with Aβ amyloid formation and to exert a strong clinical impact to the pathology of AD. The APOE gene exists in three allelic isoforms represented by APOE ε2, APOE ε3, and APOE ε4. Carriers of the APOE ε4 variant display a gene dose-dependent increased risk of developing the disease. Aβ amyloids are formed via a nucleation-dependent mechanism where free monomers are added onto a nucleus in a template-dependent manner. Using a combination of surface plasmon resonance and thioflavin-T assays, we here show that ApoE can target the process of fibril elongation and that its interference effectively prevents amyloid maturation. We expose a complex equilibrium where the concentration of ApoE, Aβ monomers, and the amount of already formed Aβ fibrils will affect the relative proportion and formation rate of mature amyloids versus alternative assemblies. The result illustrates a mechanism which may affect both the clearance rate of Aβ assemblies in vivo and the population of cytotoxic Aβ assemblies.

Keywords
abeta, amyloid, apolipoprotein E, elongation, surface plasmon resonance
National Category
Basic Medicine Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
biological chemistry
Identifiers
urn:nbn:se:umu:diva-165305 (URN)10.1111/febs.15075 (DOI)31571352 (PubMedID)
Available from: 2019-11-20 Created: 2019-11-20 Last updated: 2019-11-20
Brännström, K., Gharibyan, A. L., Islam, T., Iakovleva, I., Nilsson, L., Lee, C. C., . . . Olofsson, A. (2018). Scanning electron microscopy as a tool for evaluating morphology of amyloid structures formed on surface plasmon resonance chips. Data in Brief, 19, 1166-1170
Open this publication in new window or tab >>Scanning electron microscopy as a tool for evaluating morphology of amyloid structures formed on surface plasmon resonance chips
Show others...
2018 (English)In: Data in Brief, E-ISSN 2352-3409, Vol. 19, p. 1166-1170Article in journal (Refereed) Published
Abstract [en]

We demonstrate the use of Scanning Electron microscopy (SEM) in combination with Surface Plasmon Resonance (SPR) to probe and verify the formation of amyloid and its morphology on an SPR chip. SPR is a technique that measures changes in the immobilized weight on the chip surface and is frequently used to probe the formation and biophysical properties of amyloid structures. In this context it is of interest to also monitor the morphology of the formed structures. The SPR chip surface is made of a layer of gold, which represent a suitable material for direct analysis of the surface using SEM. The standard SPR chip used here (CM5-chip, GE Healthcare, Uppsala, Sweden) can easily be disassembled and directly analyzed by SEM. In order to verify the formation of amyloid fibrils in our experimental conditions we analyzed also in-solution produced structures by using Transmission Electron Microscopy (TEM). For further details and experimental findings, please refer to the article published in Journal of Molecular Biology, (Brännström K. et al., 2018) [1].

Place, publisher, year, edition, pages
Elsevier, 2018
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-149049 (URN)10.1016/j.dib.2018.05.129 (DOI)000449869100149 ()30228999 (PubMedID)2-s2.0-85047834173 (Scopus ID)
Note

Refers to: Kristoffer Brännström, Tohidul Islam, Anna L. Gharibyan, Irina Iakovleva, Lina Nilsson, Cheng Choo Lee, Linda Sandblad, Annelie Pamrén, Anders Olofsson. The Properties of Amyloid-β Fibrils Are Determined by their Path of Formation. Journal of Molecular Biology, Volume 430, Issue 13, 22 June 2018, Pages 1940-1949

Available from: 2018-06-14 Created: 2018-06-14 Last updated: 2019-02-04Bibliographically approved
Hakobyan, G., Davtyan, H., Harutyunyan, K., Alexanyan, K., Amirkhanyan, Y., Gharibyan, A. L., . . . Tadevosyan, Y. (2018). Similarities in Blood Mononuclear Cell Membrane Phospholipid Profiles During Malignancy. Medical Sciences, 6(4), Article ID 105.
Open this publication in new window or tab >>Similarities in Blood Mononuclear Cell Membrane Phospholipid Profiles During Malignancy
Show others...
2018 (English)In: Medical Sciences, ISSN 2076-3271, Vol. 6, no 4, article id 105Article in journal (Refereed) Published
Abstract [en]

Phospholipids (PLs), key elements of cellular membranes, are regulated reciprocally with membrane proteins and can act as sensors for alterations in physiological or pathological states of cells including initiation and development of cancer. On the other hand, peripheral blood mononuclear cells (MNCs) play an important role in antitumor immune response by reacting to cancerous modifications in distant organs. In the current study, we tested the hypothesis that tumor initiation and development are reflected in the alteration pattern of the MNC PL component. We analyzed MNC membrane PL fractions in samples from healthy individuals and from patients with diverse types of cancers to reveal possible alterations induced by malignancy. Compared to healthy controls, the cancer samples demonstrated shifts in several membrane PL profiles. In particular, when analyzing cancer data pooled together, there were significantly higher levels in lysophosphatidylcholine, phosphatidylcholine, and phosphatidylethanolamine fractions, and significantly lower quantities in phosphatidylinositol, phosphatidylserine, and phosphatidic acid fractions in cancer samples compared to controls. The levels of sphingomyelins and diphosphatidylglycerols were relatively unaffected. Most of the differences in PLs were sustained during the analysis of individual cancers such as breast cancer and chronic lymphocytic leukemia. Our findings suggest the presence of a common pattern of changes in MNC PLs during malignancy.

Place, publisher, year, edition, pages
MDPI, 2018
Keywords
cancers, mononuclear cells, plasma membrane, phospholipids, biomarkers
National Category
Cell and Molecular Biology Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-154242 (URN)10.3390/medsci6040105 (DOI)30477187 (PubMedID)
Available from: 2018-12-14 Created: 2018-12-14 Last updated: 2018-12-17Bibliographically approved
Brännström, K., Islam, T., Gharibyan, A. L., Iakovleva, I., Nilsson, L., Lee, C. C., . . . Olofsson, A. (2018). The Properties of Amyloid-β Fibrils Are Determined by their Path of Formation. Journal of Molecular Biology, 430(13), 1940-1949
Open this publication in new window or tab >>The Properties of Amyloid-β Fibrils Are Determined by their Path of Formation
Show others...
2018 (English)In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 430, no 13, p. 1940-1949Article in journal (Refereed) Published
Abstract [en]

Fibril formation of the amyloid-β peptide (Aβ) follows a nucleation-dependent polymerization process and is associated with Alzheimer's disease. Several different lengths of Aβ are observed in vivo, but Aβ1-40 and Aβ1-42 are the dominant forms. The fibril architectures of Aβ1-40 and Aβ1-42 differ and Aβ1-42 assemblies are generally considered more pathogenic. We show here that monomeric Aβ1-42 can be cross-templated and incorporated into the ends of Aβ1-40 fibrils, while incorporation of Aβ1-40 monomers into Aβ1-42 fibrils is very poor. We also show that via cross-templating incorporated Aβ monomers acquire the properties of the parental fibrils. The suppressed ability of Aβ1-40 to incorporate into the ends of Aβ1-42 fibrils and the capacity of Aβ1-42 monomers to adopt the properties of Aβ1-40 fibrils may thus represent two mechanisms reducing the total load of fibrils having the intrinsic, and possibly pathogenic, features of Aβ1-42 fibrils in vivo. We also show that the transfer of fibrillar properties is restricted to fibril-end templating and does not apply to cross-nucleation via the recently described path of surface-catalyzed secondary nucleation, which instead generates similar structures to those acquired via de novo primary nucleation in the absence of catalyzing seeds. Taken together these results uncover an intrinsic barrier that prevents Aβ1-40 from adopting the fibrillar properties of Aβ1-42 and exposes that the transfer of properties between amyloid-β fibrils are determined by their path of formation.

Place, publisher, year, edition, pages
Elsevier, 2018
Keywords
Aβ, Cross-templating, Fibril, Surface Plasmon resonance, Thioflavin-T
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-148050 (URN)10.1016/j.jmb.2018.05.001 (DOI)29751013 (PubMedID)2-s2.0-85047103029 (Scopus ID)
Available from: 2018-06-14 Created: 2018-06-14 Last updated: 2018-06-14Bibliographically approved
Nilsson, L., Pamrén, A., Islam, T., Brännström, K., Golchin, S. A., Pettersson, N., . . . Olofsson, A. (2018). Transthyretin Interferes with Aβ Amyloid Formation by Redirecting Oligomeric Nuclei into Non-Amyloid Aggregates. Journal of Molecular Biology, 430(17), 2722-2733
Open this publication in new window or tab >>Transthyretin Interferes with Aβ Amyloid Formation by Redirecting Oligomeric Nuclei into Non-Amyloid Aggregates
Show others...
2018 (English)In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 430, no 17, p. 2722-2733Article in journal (Refereed) Published
Abstract [en]

The pathological Aβ aggregates associated with Alzheimer's disease follow a nucleation-dependent path of formation. A nucleus represents an oligomeric assembly of Aβ peptides that acts as a template for subsequent incorporation of monomers to form a fibrillar structure. Nuclei can form de novo or via surface-catalyzed secondary nucleation, and the combined rates of elongation and nucleation control the overall rate of fibril formation. Transthyretin (TTR) obstructs Aβ fibril formation in favor of alternative non-fibrillar assemblies, but the mechanism behind this activity is not fully understood. This study shows that TTR does not significantly disturb fibril elongation; rather, it effectively interferes with the formation of oligomeric nuclei. We demonstrate that this interference can be modulated by altering the relative contribution of elongation and nucleation, and we show how TTR's effects can range from being essentially ineffective to almost complete inhibition of fibril formation without changing the concentration of TTR or monomeric Aβ.

Place, publisher, year, edition, pages
Elsevier, 2018
Keywords
Aβ, Surface Plasmon Resonance, Thioflavin-T, amyloid, transthyretin
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-148930 (URN)10.1016/j.jmb.2018.06.005 (DOI)000441645300013 ()29890120 (PubMedID)
Funder
The Dementia Association - The National Association for the Rights of the DementedThe Kempe FoundationsSwedish Research CouncilMagnus Bergvall FoundationTorsten Söderbergs stiftelse
Available from: 2018-06-14 Created: 2018-06-14 Last updated: 2018-09-05Bibliographically approved
Iakovleva, I., Brännström, K., Nilsson, L., Gharibyan, A., Begum, A., Intissar, A., . . . Olofsson, A. (2015). Enthalpic Forces Correlate with Selectivity of Transthyretin-Stabilizing Ligands in Human Plasma. Journal of Medicinal Chemistry, 58(16), 6507-6515
Open this publication in new window or tab >>Enthalpic Forces Correlate with Selectivity of Transthyretin-Stabilizing Ligands in Human Plasma
Show others...
2015 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 58, no 16, p. 6507-6515Article in journal (Refereed) Published
Abstract [en]

The plasma protein transthyretin (TTR) is linked to human amyloidosis. Dissociation of its native tetrameric assembly is a rate-limiting step in the conversion from a native structure into a pathological amyloidogenic fold. Binding of small molecule ligands within the thyroxine binding site of TTR can stabilize the tetrameric integrity and is a potential therapeutic approach. However, through the characterization of nine different tetramer-stabilizing ligands we found that unspecific binding to plasma components might significantly compromise ligand efficacy. Surprisingly the binding strength between a particular ligand and TTR does not correlate well with its selectivity in plasma. However, through analysis of the thermodynamic signature using isothermal titration calorimetry we discovered a better correlation between selectivity and the enthalpic component of the interaction. This is of specific interest in the quest for more efficient TTR stabilizers, but a high selectivity is an almost universally desired feature within drug design and the finding might have wide-ranging implications for drug design.

Keywords
transthyretin, entalpic, enthropic
National Category
Medicinal Chemistry
Research subject
biological chemistry
Identifiers
urn:nbn:se:umu:diva-106724 (URN)10.1021/acs.jmedchem.5b00544 (DOI)000360415800015 ()26214366 (PubMedID)
Available from: 2015-08-04 Created: 2015-08-04 Last updated: 2018-06-07Bibliographically approved
Brännström, K., Lindhagen-Persson, M., Gharibyan, A. L., Iakovleva, I., Vestling, M., Sellin, M. E., . . . Olofsson, A. (2014). A Generic Method for Design of Oligomer-Specific Antibodies. PLoS ONE, 9(3), e90857
Open this publication in new window or tab >>A Generic Method for Design of Oligomer-Specific Antibodies
Show others...
2014 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 3, p. e90857-Article in journal (Refereed) Published
Abstract [en]

Antibodies that preferentially and specifically target pathological oligomeric protein and peptide assemblies, as opposed to their monomeric and amyloid counterparts, provide therapeutic and diagnostic opportunities for protein misfolding diseases. Unfortunately, the molecular properties associated with oligomer-specific antibodies are not well understood, and this limits targeted design and development. We present here a generic method that enables the design and optimisation of oligomer-specific antibodies. The method takes a two-step approach where discrimination between oligomers and fibrils is first accomplished through identification of cryptic epitopes exclusively buried within the structure of the fibrillar form. The second step discriminates between monomers and oligomers based on differences in avidity. We show here that a simple divalent mode of interaction, as within e. g. the IgG isotype, can increase the binding strength of the antibody up to 1500 times compared to its monovalent counterpart. We expose how the ability to bind oligomers is affected by the monovalent affinity and the turnover rate of the binding and, importantly, also how oligomer specificity is only valid within a specific concentration range. We provide an example of the method by creating and characterising a spectrum of different monoclonal antibodies against both the A beta peptide and alpha-synuclein that are associated with Alzheimer's and Parkinson's diseases, respectively. The approach is however generic, does not require identification of oligomer-specific architectures, and is, in essence, applicable to all polypeptides that form oligomeric and fibrillar assemblies.

National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-88327 (URN)10.1371/journal.pone.0090857 (DOI)000332842400033 ()
Available from: 2014-06-16 Created: 2014-04-30 Last updated: 2018-06-07Bibliographically approved
Wang, C., Klechikov, A. G., Gharibyan, A. L., Wärmländer, S. K. T., Jarvet, J., Zhao, L., . . . Morozova-Roche, L. A. (2014). The role of pro-inflammatory S100A9 in Alzheimer's disease amyloid-neuroinflammatory cascade. Acta Neuropathologica, 127(4), 507-522
Open this publication in new window or tab >>The role of pro-inflammatory S100A9 in Alzheimer's disease amyloid-neuroinflammatory cascade
Show others...
2014 (English)In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 127, no 4, p. 507-522Article in journal (Refereed) Published
Abstract [en]

Pro-inflammatory S100A9 protein is increasingly recognized as an important contributor to inflammation-related neurodegeneration. Here, we provide insights into S100A9 specific mechanisms of action in Alzheimer's disease (AD). Due to its inherent amyloidogenicity S100A9 contributes to amyloid plaque formation together with A beta. In traumatic brain injury (TBI) S100A9 itself rapidly forms amyloid plaques, which were reactive with oligomer-specific antibodies, but not with A beta and amyloid fibrillar antibodies. They may serve as precursor-plaques for AD, implicating TBI as an AD risk factor. S100A9 was observed in some hippocampal and cortical neurons in TBI, AD and non-demented aging. In vitro S100A9 forms neurotoxic linear and annular amyloids resembling A beta protofilaments. S100A9 amyloid cytotoxicity and native S100A9 pro-inflammatory signaling can be mitigated by its co-aggregation with A beta, which results in a variety of micron-scale amyloid complexes. NMR and molecular docking demonstrated transient interactions between native S100A9 and A beta. Thus, abundantly present in AD brain pro-inflammatory S100A9, possessing also intrinsic amyloidogenic properties and ability to modulate A beta aggregation, can serve as a link between the AD amyloid and neuroinflammatory cascades and as a prospective therapeutic target.

Keywords
A beta, Alzheimer's disease, Amyloid, Cytotoxicity, Neuroinflammation, S100A9, Traumatic brain injury
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-88313 (URN)10.1007/s00401-013-1208-4 (DOI)000332957400004 ()
External cooperation:
Note

Erratum available at http://dx.doi.org/10.1007/s00401-014-1316-9

Available from: 2014-06-17 Created: 2014-04-30 Last updated: 2018-06-07Bibliographically approved
Gharibyan, A. (2012). Amyloids here, amyloids there…What’s wrong with them?. (Doctoral dissertation). Umeå: Umeå University
Open this publication in new window or tab >>Amyloids here, amyloids there…What’s wrong with them?
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Amyloid formation is inherent property of proteins which under certain circumstances can become a pathologic feature of a group of diseases called amyloidosis. There are about 30 known human amyloidosis and more than 27 identified proteins involved in these pathologies.  Besides these proteins, there are a growing number of proteins non-related to diseases shown to form amyloid-like structures in vitro, which make them excellent tools for studying amyloid formation mechanisms, physicochemical properties of different amyloid species and the nature of their influence on tissues and cells.  It is important to understand the mechanisms by which amyloids interact with different types of cells, as the leading hypothesis in amyloid field suggests that amyloids and especially their intermediate states are the main harmful, toxic species causing tissue and cell degeneration.

Using de-novo synthesized protein albebetin as a model of amyloidogenic protein, we demonstrated that it forms amyloid-like structures under physiological conditions (pH 7 and 37°C). During aggregation it forms 2 different types of intermediate oligomers — cross-b sheet containing and lacking β-sheet oligomers. Only the former induces cellular toxicity in a dose dependent manner. Further aggregation leads to the formation of fully mature amyloid-like fibrils, which are not toxic to the cells during studied period of incubation.

Another model protein in our studies was hen egg white lysozyme, which readily forms amyloid under denaturing conditions (pH 2,2 and 57°C). In contrast to albebetin and many other proteins reported in the literature, we showed that both oligomers and mature fibrils from hen lysozyme affect cell viability. Targeting different mechanisms involved in cellular death, we revealed that oligomers induce slow and apoptotic-like cell death, while mature fibrils cause rapid and mainly necrotic-like cellular death.   

One of the important aspects of amyloid studies is to develop measures for inhibiting or re-directing the process of amyloid formation to abolish or neutralize toxic amyloid species. Among the agents having inhibitory or modulatory properties small, phenol containing molecules are widely studied. We investigated the effect of the novel nootropic drug noopept on amyloid formation process of α-synuclein, as this drug is a small dipeptide containing a phenol ring. We showed that noopept is able to modulate amyloid formation process by accelerating it to rapid conversion of α-synuclein into fully mature fibrils, thus eliminating the stage of population of toxic oligomeric species.  Using wide range of cytotoxicity assays we showed that amyloid-like fibrils formed in the presence of noopept have no cytotoxic properties.  As this medicine is becoming popular and freely available in some countries as a cognitive enhancer, neuroprotective and nootropic agent, further detailed investigations and clinical trials are needed to assess the safety and benefit of noopept in particular for the patients with amyloid related neurodegenerative diseases (such as Parkinson’s or Alzheimer’s diseases).    

While in vitro models are useful to study some specific aspects of protein aggregation, their properties and effects on cell viability, it is very difficult or practically impossible to create an absolutely accurate model of in vivo situation. Therefore, it is important to turn to in vivo/ex vivo studies to relate the knowledge accumulated from in vitro studies to the real situation in the body.

Using human brain hippocampus tissues from individuals with Alzheimer’s disease, we found that besides well-known and widely accepted main pathological hallmark — Ab peptide deposition, S100A9 and S100A8 pro-inflammatory calcium-binding proteins are also localized in the plaques and in surrounding tissues and very explicitly co-localized with Ab. Moreover, we found the presence of S100A9 within the neuronal cells, which has not been reported before and can be an important clue for understanding the mechanisms of neurodegeneration. In vitro cytotoxicity studies showed that S100A9 protein can efficiently induce cytotoxicity when added exogenously to the neuronal cell culture. These findings suggest that S100A8 and S100A9 proteins play an important role in Alzheimer’s pathology, and potentially can be candidates for the amyloid plaque formation and neurodegeneration. Whether they are associated with inflammatory processes underlying the early onset of disease or produced and accumulated as a consequence of A-beta induced pathology remain to be clarified.

We found that Alzheimer’s disease is not the only pathology associated with A-beta and S100A9 deposition in a form of plaques. Immunohistochemical studies of an aortic valve surgically removed from a patient with aortic stenosis revealed plaque-like structures positively stained with A-beta and S100A9 proteins. These areas are also positively stained with fibril-specific antibodies as well as with Congo red, which also shows very distinct apple-green birefringence under the polarized light. Besides, there is intracellular localization and co-localization of both proteins in interstitial cells throughout the whole fibrous tissue of the valve. The presented case report is the first finding suggesting inflammatory protein S100A9 as well as A-beta peptide as potential candidates for amyloid formation in aortic stenosis valves.  We suggest that there is a specific interaction between A-beta and S100A9 during amyloid formation, which can be involved in amyloid-associated pathology in various tissues and organs in the body, which can potentially be caused by inflammatory processes, particularly by its chronic, long lasting forms.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2012. p. 67
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1511
Keywords
Amyloids, oligomers, fibrils, cytotoxicity, Alzheimer's disease, Aortic stenosis, S100A9
National Category
Cell and Molecular Biology Other Basic Medicine
Research subject
Medical Biochemistry
Identifiers
urn:nbn:se:umu:diva-55621 (URN)978-91-7459-447-8 (ISBN)
Public defence
2012-06-15, KB3B1, KBC, Umeå University, Umeå, 10:00 (English)
Opponent
Supervisors
Available from: 2012-05-25 Created: 2012-05-24 Last updated: 2018-06-08Bibliographically approved
Vogl, T., Gharibyan, A. & Morozova-Roche, L. (2012). Pro-Inflammatory S100A8 and S100A9 Proteins: Self-Assembly into Multifunctional Native and Amyloid Complexes. International Journal of Molecular Sciences, 13(3), 2893-2917
Open this publication in new window or tab >>Pro-Inflammatory S100A8 and S100A9 Proteins: Self-Assembly into Multifunctional Native and Amyloid Complexes
2012 (English)In: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 13, no 3, p. 2893-2917Article in journal (Refereed) Published
Abstract [en]

S100A8 and S100A9 are EF-hand Ca2+ binding proteins belonging to the S100 family. They are abundant in cytosol of phagocytes and play critical roles in numerous cellular processes such as motility and danger signaling by interacting and modulating the activity of target proteins. S100A8 and S100A9 expression levels increased in many types of cancer, neurodegenerative disorders, inflammatory and autoimmune diseases and they are implicated in the numerous disease pathologies. The Ca2+ and Zn2+-binding properties of S100A8/A9 have a pivotal influence on their conformation and oligomerization state, including self-assembly into homo- and heterodimers, tetramers and larger oligomers. Here we review how the unique chemical and conformational properties of individual proteins and their structural plasticity at the quaternary level account for S100A8/A9 functional diversity. Additional functional diversification occurs via non-covalent assembly into oligomeric and fibrillar amyloid complexes discovered in the aging prostate and reproduced in vitro. This process is also regulated by Ca2+ and Zn2+-binding and effectively competes with the formation of the native complexes. High intrinsic amyloid-forming capacity of S100A8/A9 proteins may lead to their amyloid depositions in numerous ailments characterized by their elevated expression patterns and have additional pathological significance requiring further thorough investigation.

Keywords
S100A8, S100A9, S100 proteins, amyloid, inflammation, cancer, self-assembly, calcium-binding, calprotectin
National Category
Structural Biology Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-55620 (URN)10.3390/ijms13032893 (DOI)000302174500024 ()
Available from: 2012-05-24 Created: 2012-05-24 Last updated: 2018-06-08Bibliographically approved
Organisations

Search in DiVA

Show all publications