An Intermediate Structure in the Thermal Unfolding of the GTPase Domain of Human Septin 4 (SEPT4/Bradeion-) Forms Amyloid-like Filaments in Vitro

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• 作者：Wanius Garcia ; Ana Paula Ulian de Araú ; jo ; Flá ; vio Lara ; Debora Foguel ; Manami Tanaka ; Tomoo Tanaka ; Richard Charles Garratt
• 刊名：Biochemistry
• 出版年：2007
• 出版时间：October 2, 2007
• 年：2007
• 卷：46
• 期：39
• 页码：11101 - 11109
• 全文大小：635K
• 年卷期：v.46,no.39(October 2, 2007)
• ISSN：1520-4995

文摘

SEPT4 is a member of the mammalian septin family of GTPases. Mammalian septins areconserved proteins which form heteropolymers in vivo and which are implicated in a variety of cellularfunctions such as cytokinesis, exocytosis, and vesicle trafficking. However, their structural properties andmodes of action are largely unknown. There is a limited, but as yet inconclusive, amount of experimentaldata suggesting that SEPT4 may accumulate in tau-based filamentous deposits and cytoplasmic inclusionsin Alzheimer's and Parkinson's disease, respectively. Here we report an intermediate structure of theGTPase domain of human SEPT4 (SEPT4-G) during unfolding transitions induced by temperature. Thispartially unfolded intermediate, which is rich in -sheet and free of bound nucleotide, was plagued byirreversible aggregation. The aggregates have the ability to bind specific dyes such as Congo red andthioflavin-T, suggesting they are amyloid in nature. Under electron microscopy, fibers of variable diameterextending for several micrometers in length can be visualized. This is the first report of amyloid formationby a septin or domain thereof, and the capacity of SEPT4-G to form such fibrillar aggregates may shedsome light on the current discussion concerning the formation of homo- and heteropolymers of septins invitro.