Amyloid aggregates are found in many neurodegenerative diseases, including Huntington's, Alzheimer's, and prion diseases. The precise role of the aggregates in disease progression has been difficult to elucidate because of the diversity of aggregated states they can adopt. Here, we study the formation of fibrils and oligomers by exon 1 of huntingtin protein. We show that the oligomer states are consistent with polymer micelles that are limited in size by the stretching entropy of the polyglutamine region. The model shows how the sequences flanking the amyloid core modulate aggregation behavior. The N17 region promotes aggregation through weakly attractive interactions, whereas the C38 tail opposes aggregation via steric repulsion. We also show that the energetics of cross-beta stacking by polyglutamine would produce fibrils with many alignment defects, but minor perturbations from the flanking sequences are sufficient to reduce the defects to the level observed in experiment. We conclude with a discussion of the implications of this model for other amyloid-forming molecules.
机构:
West Virginia Univ, C Eugene Bennett Dept Chem, 217 Clark Hall, Morgantown, WV 26506 USAWest Virginia Univ, C Eugene Bennett Dept Chem, 217 Clark Hall, Morgantown, WV 26506 USA
Groover, Sharon
Valentine, Stephen J.
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West Virginia Univ, C Eugene Bennett Dept Chem, 217 Clark Hall, Morgantown, WV 26506 USAWest Virginia Univ, C Eugene Bennett Dept Chem, 217 Clark Hall, Morgantown, WV 26506 USA
Valentine, Stephen J.
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Legleiter, Justin
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES,
2021,
1863
(01):
机构:
Dar Al Uloom Univ, Coll Med, Dept Basic Med Sci, Riyadh, Saudi Arabia
Al Ain Univ, AAU Hlth, Abu Dhabi, U Arab Emirates
Al Ain Univ, Biomed Res Ctr, Abu Dhabi, U Arab Emirates
Al Ain Univ, Coll Pharm, Abu Dhabi Campus, Abu Dhabi, U Arab EmiratesDar Al Uloom Univ, Coll Med, Dept Basic Med Sci, Riyadh, Saudi Arabia
Ramadan, Azza
Mohammed, Abuelnor
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Dar Al Uloom Univ, Coll Med, Dept Basic Med Sci, Riyadh, Saudi Arabia
Huazhong Univ Sci & Technol, Tongji Med Coll, Sch Basic Med Sci, Dept Histol & Embryol, 13 Hangkong Rd, Wuhan 430030, Peoples R ChinaDar Al Uloom Univ, Coll Med, Dept Basic Med Sci, Riyadh, Saudi Arabia
Mohammed, Abuelnor
Elnour, Asim Ahmed
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机构:
Al Ain Univ, Coll Pharm, Program Clin Pharm, Abu Dhabi campus, Abu Dhabi, U Arab Emirates
Al Ain Univ, AAU Hlth, Abu Dhabi, U Arab Emirates
Al Ain Univ, Biomed Res Ctr, Abu Dhabi, U Arab EmiratesDar Al Uloom Univ, Coll Med, Dept Basic Med Sci, Riyadh, Saudi Arabia
Elnour, Asim Ahmed
Sadeq, Adel
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Al Ain Univ, Coll Pharm, Program Clin Pharm, Al Ain, U Arab EmiratesDar Al Uloom Univ, Coll Med, Dept Basic Med Sci, Riyadh, Saudi Arabia
Sadeq, Adel
Al Mazrouei, Nadia
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Univ Sharjah, Fac Pharm, Dept Pharm Practice & Pharmacotherapeut, Sharjah, U Arab EmiratesDar Al Uloom Univ, Coll Med, Dept Basic Med Sci, Riyadh, Saudi Arabia
Al Mazrouei, Nadia
Alkaabi, Maisoun
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Royal Womens Hosp, New Med Ctr NMC, Abu Dhabi, U Arab EmiratesDar Al Uloom Univ, Coll Med, Dept Basic Med Sci, Riyadh, Saudi Arabia
Alkaabi, Maisoun
Al-Kubaisi, Khalid Awad
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Univ Sharjah, Coll Pharm, Dept Pharm Practice & Pharmacotherapeut, Sharjah, U Arab EmiratesDar Al Uloom Univ, Coll Med, Dept Basic Med Sci, Riyadh, Saudi Arabia
Al-Kubaisi, Khalid Awad
Beshir, Semira Abdi
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Dubai Pharm Coll Girls, Dept Clin Pharm & Pharmacotherapeut, Dubai, U Arab EmiratesDar Al Uloom Univ, Coll Med, Dept Basic Med Sci, Riyadh, Saudi Arabia
Beshir, Semira Abdi
Menon, Vineetha
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Gulf Med Univ, Coll Pharm, Dept Pharm Practice, Ajman, U Arab EmiratesDar Al Uloom Univ, Coll Med, Dept Basic Med Sci, Riyadh, Saudi Arabia
Menon, Vineetha
Alamoodi, Abdulla
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Abu Dhabi Hlth Serv SEHA, Ambulatory Healthcare Serv, Acad Affairs, Abu Dhabi, U Arab EmiratesDar Al Uloom Univ, Coll Med, Dept Basic Med Sci, Riyadh, Saudi Arabia
Alamoodi, Abdulla
Sam, Kishore Ganana
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Dept Clin Pharm & Pharmacotherapeut, Dubai, U Arab EmiratesDar Al Uloom Univ, Coll Med, Dept Basic Med Sci, Riyadh, Saudi Arabia
Sam, Kishore Ganana
Saeed, Ali Awadallah Ali Mohamed
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Natl Univ Sudan, Fac Clin & Ind Pharm, Mycetoma Res Ctr, Dept Pharmacol, Khartoum, SudanDar Al Uloom Univ, Coll Med, Dept Basic Med Sci, Riyadh, Saudi Arabia
Saeed, Ali Awadallah Ali Mohamed
Abdalla, Sami Fatehi
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Univ Almaarefa, Coll Med, Clin Dept, Riyadh, Saudi ArabiaDar Al Uloom Univ, Coll Med, Dept Basic Med Sci, Riyadh, Saudi Arabia
Abdalla, Sami Fatehi
Hussein, Samah Mohammed
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Qassim Univ, Unaizah Coll Pharm, Dept Pharm Practice, Buraydah 52571, Saudi ArabiaDar Al Uloom Univ, Coll Med, Dept Basic Med Sci, Riyadh, Saudi Arabia
机构:
West Virginia Univ, C Eugene Bennett Dept Chem, Morgantown, WV 26506 USAWest Virginia Univ, C Eugene Bennett Dept Chem, Morgantown, WV 26506 USA
Beasley, Maryssa A.
Groover, Sharon E.
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机构:
West Virginia Univ, C Eugene Bennett Dept Chem, Morgantown, WV 26506 USAWest Virginia Univ, C Eugene Bennett Dept Chem, Morgantown, WV 26506 USA
Groover, Sharon E.
Legleiter, Justin A.
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机构:
West Virginia Univ, C Eugene Bennett Dept Chem, Morgantown, WV 26506 USA
West Virginia Univ, Robert C Byrd Hlth Sci Ctr, Blanchette Rockefeller Neurosci Inst, Morgantown, WV 26506 USAWest Virginia Univ, C Eugene Bennett Dept Chem, Morgantown, WV 26506 USA
机构:
W Virginia Univ, C Eugene Bennett Dept Chem, Morgantown, WV 26505 USA
W Virginia Univ, WVnanoSAFE, Morgantown, WV 26505 USAW Virginia Univ, C Eugene Bennett Dept Chem, Morgantown, WV 26505 USA
Chaibva, Maxmore
Burke, Kathleen A.
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机构:
W Virginia Univ, C Eugene Bennett Dept Chem, Morgantown, WV 26505 USAW Virginia Univ, C Eugene Bennett Dept Chem, Morgantown, WV 26505 USA
Burke, Kathleen A.
Legleiter, Justin
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机构:
W Virginia Univ, C Eugene Bennett Dept Chem, Morgantown, WV 26505 USA
W Virginia Univ, WVnanoSAFE, Morgantown, WV 26505 USA
W Virginia Univ, Ctr Neurosci, Morgantown, WV 26505 USAW Virginia Univ, C Eugene Bennett Dept Chem, Morgantown, WV 26505 USA