Unmasking determinants of specificity in the human kinome

TY - JOUR

T1 - Unmasking determinants of specificity in the human kinome

AU - Creixell, Pau

AU - Palmeri, Antonio

AU - Miller, Chad J

AU - Lou, Hua Jane

AU - Santini, Cristina C.

AU - Nielsen, Morten

AU - Turk, Benjamin E

AU - Linding, Rune

N1 - Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

PY - 2015/9/24

Y1 - 2015/9/24

N2 - Protein kinases control cellular responses to environmental cues by swift and accurate signal processing. Breakdowns in this high-fidelity capability are a driving force in cancer and other diseases. Thus, our limited understanding of which amino acids in the kinase domain encode substrate specificity, the so-called determinants of specificity (DoS), constitutes a major obstacle in cancer signaling. Here, we systematically discover several DoS and experimentally validate three of them, named the αC1, αC3, and APE-7 residues. We demonstrate that DoS form sparse networks of non-conserved residues spanning distant regions. Our results reveal a likely role for inter-residue allostery in specificity and an evolutionary decoupling of kinase activity and specificity, which appear loaded on independent groups of residues. Finally, we uncover similar properties driving SH2 domain specificity and demonstrate how the identification of DoS can be utilized to elucidate a greater understanding of the role of signaling networks in cancer (Creixell et al., 2015 [this issue of Cell]).

AB - Protein kinases control cellular responses to environmental cues by swift and accurate signal processing. Breakdowns in this high-fidelity capability are a driving force in cancer and other diseases. Thus, our limited understanding of which amino acids in the kinase domain encode substrate specificity, the so-called determinants of specificity (DoS), constitutes a major obstacle in cancer signaling. Here, we systematically discover several DoS and experimentally validate three of them, named the αC1, αC3, and APE-7 residues. We demonstrate that DoS form sparse networks of non-conserved residues spanning distant regions. Our results reveal a likely role for inter-residue allostery in specificity and an evolutionary decoupling of kinase activity and specificity, which appear loaded on independent groups of residues. Finally, we uncover similar properties driving SH2 domain specificity and demonstrate how the identification of DoS can be utilized to elucidate a greater understanding of the role of signaling networks in cancer (Creixell et al., 2015 [this issue of Cell]).

KW - Computational Biology

KW - Humans

KW - Models, Molecular

KW - Neoplasms

KW - Protein Kinases

KW - Substrate Specificity

KW - src Homology Domains

U2 - 10.1016/j.cell.2015.08.057

DO - 10.1016/j.cell.2015.08.057

M3 - Journal article

C2 - 26388442

SN - 0092-8674

VL - 163

SP - 187

EP - 201

JO - Cell

JF - Cell

IS - 1

ER -