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ERK1/2 interaction with DHPS regulates eIF5A deoxyhypusination independently of ERK kinase activity. Cell Rep 2024 Oct 22;43(10):114831

Date

10/11/2024

Pubmed ID

39392755

Pubmed Central ID

PMC11544350

DOI

10.1016/j.celrep.2024.114831

Scopus ID

2-s2.0-85207351264 (requires institutional sign-in at Scopus site)   6 Citations

Abstract

This study explores a non-kinase effect of extracellular regulated kinases 1/2 (ERK1/2) on the interaction between deoxyhypusine synthase (DHPS) and its substrate, eukaryotic translation initiation factor 5A (eIF5A). We report that Raf/MEK/ERK activation decreases the DHPS-ERK1/2 interaction while increasing DHPS-eIF5A association in cells. We determined the cryoelectron microscopy (cryo-EM) structure of the DHPS-ERK2 complex at 3.5 Å to show that ERK2 hinders substrate entrance to the DHPS active site, subsequently inhibiting deoxyhypusination in vitro. In cells, impairing the ERK2 activation loop, but not the catalytic site, prolongs the DHPS-ERK2 interaction irrespective of Raf/MEK signaling. The ERK2 Ser-Pro-Ser motif, but not the common docking or F-site recognition sites, also regulates this complex. These data suggest that ERK1/2 dynamically regulate the DHPS-eIF5A interaction in response to Raf/MEK activity, regardless of its kinase function. In contrast, ERK1/2 kinase activity is necessary to regulate the expression of DHPS and eIF5A. These findings highlight an ERK1/2-mediated dual kinase-dependent and -independent regulation of deoxyhypusination.

Author List

Becker AE, Kochanowski P, Wu PK, Wątor E, Chen W, Guchhait K, Biela AP, Grudnik P, Park JI

Authors

Koushik Guchhait Postdoctoral Researcher 2 in the Biochemistry department at Medical College of Wisconsin
Jong-In Park PhD Professor in the Biochemistry department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Cryoelectron Microscopy
HEK293 Cells
Humans
MAP Kinase Signaling System
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
Oxidoreductases Acting on CH-NH Group Donors
Peptide Initiation Factors
Protein Binding
RNA-Binding Proteins