Autoinhibitory domains: modular effectors of cellular regulation.
Autoinhibitory domains are regions of proteins that negatively regulate the function of other domains via intramolecular interactions. Autoinhibition is a potent regulatory mechanism that provides tight "on-site" repression. The discovery of autoinhibition generates valuable clues to how a protein is regulated within a biological context. Mechanisms that counteract the autoinhibition, including proteolysis, post-translational modifications, as well as addition of proteins or small molecules in trans, often represent central regulatory pathways. In this review, we document the diversity of instances in which autoinhibition acts in cell regulation. Seven well-characterized examples (e.g., sigma(70), Ets-1, ERM, SNARE and WASP proteins, SREBP, Src) are covered in detail. Over thirty additional examples are listed. We present experimental approaches to characterize autoinhibitory domains and discuss the implications of this widespread phenomenon for biological regulation in both the normal and diseased states.
Pufall
Miles A
MA
Huntsman Cancer Institute, Department of Oncological Sciences, University of Utah, 2000 Circle of Hope, Salt Lake City 84112-5550, USA. miles.pufall@hci.utah.edu
Graves
Barbara J
BJ
D000818:Animals; D020134:Catalytic Domain / Q000502:physiology; D005057:Eukaryotic Cells / Q000378:metabolism* / Q000648:ultrastructure; D025461:Feedback, Physiological / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D006801:Humans; D008968:Molecular Conformation; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D011506:Proteins / Q000378:metabolism*
D011506:Proteins