TY - JOUR

T1 - Eukaryotic transcription factors

T2 - paradigms of protein intrinsic disorder

AU - Staby, Lasse

AU - O'Shea, Charlotte

AU - Willemoës, Martin

AU - Theisen, Frederik

AU - Kragelund, Birthe Brandt

AU - Skriver, Karen

N1 - © 2017 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society.

PY - 2017/7/12

Y1 - 2017/7/12

N2 - Gene-specific transcription factors (TFs) are key regulatory components of signaling pathways, controlling, for example, cell growth, development, and stress responses. Their biological functions are determined by their molecular structures, as exemplified by their structured DNA-binding domains targeting specific cis-acting elements in genes, and by the significant lack of fixed tertiary structure in their extensive intrinsically disordered regions. Recent research in protein intrinsic disorder (ID) has changed our understanding of transcriptional activation domains from 'negative noodles' to ID regions with function-related, short sequence motifs and molecular recognition features with structural propensities. This review focuses on molecular aspects of TFs, which represent paradigms of ID-related features. Through specific examples, we review how the ID-associated flexibility of TFs enables them to participate in large interactomes, how they use only a few hydrophobic residues, short sequence motifs, prestructured motifs, and coupled folding and binding for their interactions with co-activators, and how their accessibility to post-translational modification affects their interactions. It is furthermore emphasized how classic biochemical concepts like allostery, conformational selection, induced fit, and feedback regulation are undergoing a revival with the appreciation of ID. The review also describes the most recent advances based on computational simulations of ID-based interaction mechanisms and structural analysis of ID in the context of full-length TFs and suggests future directions for research in TF ID.

AB - Gene-specific transcription factors (TFs) are key regulatory components of signaling pathways, controlling, for example, cell growth, development, and stress responses. Their biological functions are determined by their molecular structures, as exemplified by their structured DNA-binding domains targeting specific cis-acting elements in genes, and by the significant lack of fixed tertiary structure in their extensive intrinsically disordered regions. Recent research in protein intrinsic disorder (ID) has changed our understanding of transcriptional activation domains from 'negative noodles' to ID regions with function-related, short sequence motifs and molecular recognition features with structural propensities. This review focuses on molecular aspects of TFs, which represent paradigms of ID-related features. Through specific examples, we review how the ID-associated flexibility of TFs enables them to participate in large interactomes, how they use only a few hydrophobic residues, short sequence motifs, prestructured motifs, and coupled folding and binding for their interactions with co-activators, and how their accessibility to post-translational modification affects their interactions. It is furthermore emphasized how classic biochemical concepts like allostery, conformational selection, induced fit, and feedback regulation are undergoing a revival with the appreciation of ID. The review also describes the most recent advances based on computational simulations of ID-based interaction mechanisms and structural analysis of ID in the context of full-length TFs and suggests future directions for research in TF ID.

KW - Amino Acid Sequence

KW - Animals

KW - Eukaryota

KW - Humans

KW - Intrinsically Disordered Proteins

KW - Kinetics

KW - Protein Processing, Post-Translational

KW - Thermodynamics

KW - Transcription Factors

KW - Journal Article

KW - Review

U2 - 10.1042/BCJ20160631

DO - 10.1042/BCJ20160631

M3 - Review

C2 - 28701416

VL - 474

SP - 2509

EP - 2532

JO - Biochemical Journal

JF - Biochemical Journal

SN - 0264-6021

IS - 15

ER -