PDBsum entry 4uya

Transferase

PDB id: 4uya

Contents

Protein chain

274 a.a.

Ligands

AGS

Metals

_MG ×2

Waters ×39

PDB id:

4uya

Name:

Transferase

Title:

Structure of mlk4 kinase domain with atpgammas

Structure:

Mitogen-activated protein kinase kinase kinase mlk4. Chain: a. Fragment: kinase domain with n-terminal leucine zipper 1, unp residues 115-451. Synonym: mixed lineage kinase 4. Engineered: yes. Mutation: yes. Other_details: protein dephosphorylated

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf21

Resolution:

2.80Å R-factor: 0.204 R-free: 0.261

Authors:

J.A.Read,C.Brassington,H.K.Pollard,C.Phillips,I.Green,R.Overmann, M.Collier

Key ref:

A.A.Marusiak et al. (2016). Recurrent MLK4 Loss-of-Function Mutations Suppress JNK Signaling to Promote Colon Tumorigenesis. Cancer Res, 76, 724-735. PubMed id: 26637668 DOI: 10.1158/0008-5472.CAN-15-0701-T

Date:

29-Aug-14 Release date: 30-Sep-15

Protein chain

Q5TCX8  (M3K21_HUMAN) -  Mitogen-activated protein kinase kinase kinase 21 from Homo sapiens

Seq: 1036 a.a.

Struc: 274 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.2.7.11.25 - mitogen-activated protein kinase kinase kinase.
• Reaction:
  1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H⁺
  2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H⁺

L-seryl-[protein] (Bound ligand (Het Group name = AGS) matches with 93.75% similarity) + ATP = O-phospho-L-seryl-[protein] + ADP + H(+)

L-threonyl-[protein] (Bound ligand (Het Group name = AGS) matches with 93.75% similarity) + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1158/0008-5472.CAN-15-0701-T

Cancer Res 76:724-735 (2016)

PubMed id: 26637668

Recurrent MLK4 Loss-of-Function Mutations Suppress JNK Signaling to Promote Colon Tumorigenesis.

A.A.Marusiak, N.L.Stephenson, H.Baik, E.W.Trotter, Y.Li, K.Blyth, S.Mason, P.Chapman, L.A.Puto, J.A.Read, C.Brassington, H.K.Pollard, C.Phillips, I.Green, R.Overman, M.Collier, E.Testoni, C.J.Miller, T.Hunter, O.J.Sansom, J.Brognard.

ABSTRACT

MLK4 is a member of the mixed-lineage family of kinases that regulate the JNK, p38, and ERK kinase signaling pathways. MLK4 mutations have been identified in various human cancers, including frequently in colorectal cancer, where their function and pathobiological importance have been uncertain. In this study, we assessed the functional consequences of MLK4 mutations in colon tumorigenesis. Biochemical data indicated that a majority of MLK4 mutations are loss-of-function (LOF) mutations that can exert dominant-negative effects. In seeking to understand the abrogated activity of these mutants, we elucidated a new MLK4 catalytic domain structure. To determine whether MLK4 is required to maintain tumorigenic phenotypes, we reconstituted its signaling axis in colon cancer cells harboring MLK4-inactivating mutations. We found that restoring MLK4 activity reduced cell viability, proliferation, and colony formation in vitro and delayed tumor growth in vivo. Mechanistic investigations established that restoring the function of MLK4 selectively induced the JNK pathway and its downstream targets, cJUN, ATF3, and the cyclin-dependent kinase inhibitors CDKN1A and CDKN2B. Our work indicates that MLK4 is a novel tumor-suppressing kinase harboring frequent LOF mutations that lead to diminished signaling in the JNK pathway and enhanced proliferation in colon cancer. Cancer Res; 76(3); 724-35. ©2015 AACR.