Ancestral reconstruction reveals mechanisms of ERK regulatory evolution
Abstract
Protein kinases are crucial to coordinate cellular decisions and therefore their activities are strictly regulated. Previously we used ancestral reconstruction to determine how CMGC group kinase specificity evolved (Howard et al., 2014). In the present study, we reconstructed ancestral kinases to study the evolution of regulation, from the inferred ancestor of CDKs and MAPKs, to modern ERKs. Kinases switched from high to low autophosphorylation activity at the transition to the inferred ancestor of ERKs 1 and 2. Two synergistic amino acid changes were sufficient to induce this change: shortening of the β3-αC loop and mutation of the gatekeeper residue. Restoring these two mutations to their inferred ancestral state led to a loss of dependence of modern ERKs 1 and 2 on the upstream activating kinase MEK in human cells. Our results shed light on the evolutionary mechanisms that led to the tight regulation of a kinase that is central in development and disease.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Aug 13, 2019
- Source ID
- 10.7554/elife.38805
Entities
People
- Benjamin E Turk
- Dajun Sang
- Hua Jane Lou
- John D. Chodera
- Liam Holt
- Myvizhi E Selvan
- Rafal Wiewiora
- Sudarshan Pinglay
- Zeynep H. Gümüş
Organizations
- Icahn School of Medicine at Mount Sinai
- Memorial Sloan Kettering Cancer Center
- National Cancer Institute
- National Institute of General Medical Sciences
- The Vilcek Foundation
- United States Department of Defense
- Yale University