TY - JOUR
T1 - Mutations linked to neurological disease enhance self-association of low-complexity protein sequences
AU - Zhou, Xiaoming
AU - Sumrow, Lily
AU - Tashiro, Kyuto
AU - Sutherland, Lillian
AU - Liu, Daifei
AU - Qin, Tian
AU - Kato, Masato
AU - Liszczak, Glen
AU - McKnight, Steven L.
N1 - Publisher Copyright:
© 2022 American Association for the Advancement of Science. All rights reserved.
PY - 2022/7/1
Y1 - 2022/7/1
N2 - Protein domains of low sequence complexity do not fold into stable, three-dimensional structures. Nevertheless, proteins with these sequences assist in many aspects of cell organization, including assembly of nuclear and cytoplasmic structures not surrounded by membranes. The dynamic nature of these cellular assemblies is caused by the ability of low-complexity domains (LCDs) to transiently self-associate through labile, cross-b structures. Mechanistic studies useful for the study of LCD self-association have evolved over the past decade in the form of simple assays of phase separation. Here, we have used such assays to demonstrate that the interactions responsible for LCD self-association can be dictated by labile protein structures poised close to equilibrium between the folded and unfolded states. Furthermore, missense mutations causing Charcot-Marie-Tooth disease, frontotemporal dementia, and Alzheimer’s disease manifest their pathophysiology in vitro and in cultured cell systems by enhancing the stability of otherwise labile molecular structures formed upon LCD self-association.
AB - Protein domains of low sequence complexity do not fold into stable, three-dimensional structures. Nevertheless, proteins with these sequences assist in many aspects of cell organization, including assembly of nuclear and cytoplasmic structures not surrounded by membranes. The dynamic nature of these cellular assemblies is caused by the ability of low-complexity domains (LCDs) to transiently self-associate through labile, cross-b structures. Mechanistic studies useful for the study of LCD self-association have evolved over the past decade in the form of simple assays of phase separation. Here, we have used such assays to demonstrate that the interactions responsible for LCD self-association can be dictated by labile protein structures poised close to equilibrium between the folded and unfolded states. Furthermore, missense mutations causing Charcot-Marie-Tooth disease, frontotemporal dementia, and Alzheimer’s disease manifest their pathophysiology in vitro and in cultured cell systems by enhancing the stability of otherwise labile molecular structures formed upon LCD self-association.
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U2 - 10.1126/science.abn5582
DO - 10.1126/science.abn5582
M3 - Article
C2 - 35771920
AN - SCOPUS:85133219102
SN - 0036-8075
VL - 377
JO - Science
JF - Science
IS - 6601
M1 - eabn5582
ER -