PDBsum entry 4lgd

Signaling protein

PDB id: 4lgd

Contents

Protein chains

350 a.a.

47 a.a.

29 a.a.

48 a.a.

40 a.a.

Ligands

ANP ×4

SO4 ×9

Metals

_NA ×3

_MG ×4

PDB id:

4lgd

Name:

Signaling protein

Title:

Structural basis for autoactivation of human mst2 kinase and its regulation by rassf5

Structure:

Serine/threonine-protein kinase 3. Chain: a, b, c, d. Fragment: kinase domain, sarah domain, unp residues 1-313, 428-491. Synonym: mammalian ste20-like protein kinase 2, mst-2, ste20-like kinase mst2, serine/threonine-protein kinase krs-1, serine/threonine- protein kinase 3 36kda subunit, mst2/n, serine/threonine-protein kinase 3 20kda subunit, mst2/c. Engineered: yes. Mutation: yes.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: stk3, krs1, mst2. Expressed in: escherichia coli. Expression_system_taxid: 469008. Gene: rassf5, nore1, rapl.

Resolution:

3.05Å R-factor: 0.202 R-free: 0.244

Authors:

X.Luo,L.Ni,D.R.Tomchick

Key ref:

L.Ni et al. (2013). Structural basis for autoactivation of human Mst2 kinase and its regulation by RASSF5. Structure, 21, 1757-1768. PubMed id: 23972470 DOI: 10.1016/j.str.2013.07.008

Date:

27-Jun-13 Release date: 18-Sep-13

Protein chains

Q13188  (STK3_HUMAN) -  Serine/threonine-protein kinase 3 from Homo sapiens

Seq: 491 a.a.

Struc: 350 a.a.*

Protein chain

Q8WWW0  (RASF5_HUMAN) -  Ras association domain-containing protein 5 from Homo sapiens

Seq: 418 a.a.

Struc: 47 a.a.

Protein chain

Q8WWW0  (RASF5_HUMAN) -  Ras association domain-containing protein 5 from Homo sapiens

Seq: 418 a.a.

Struc: 29 a.a.

Protein chain

Q8WWW0  (RASF5_HUMAN) -  Ras association domain-containing protein 5 from Homo sapiens

Seq: 418 a.a.

Struc: 48 a.a.

Protein chain

Q8WWW0  (RASF5_HUMAN) -  Ras association domain-containing protein 5 from Homo sapiens

Seq: 418 a.a.

Struc: 40 a.a.

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: Chains A, B, C, D: E.C.2.7.11.1 - non-specific serine/threonine protein 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] + ATP = O-phospho-L-seryl-[protein] (Bound ligand (Het Group name = ANP) matches with 81.25% similarity) + ADP + H(+)

L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] (Bound ligand (Het Group name = ANP) matches with 81.25% similarity) + ADP + H(+)

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

reference

DOI no: 10.1016/j.str.2013.07.008

Structure 21:1757-1768 (2013)

PubMed id: 23972470

Structural basis for autoactivation of human Mst2 kinase and its regulation by RASSF5.

L.Ni, S.Li, J.Yu, J.Min, C.A.Brautigam, D.R.Tomchick, D.Pan, X.Luo.

ABSTRACT

The tumor-suppressive Hippo pathway controls tissue homeostasis through balancing cell proliferation and apoptosis. Activation of the kinases Mst1 and Mst2 (Mst1/2) is a key upstream event in this pathway and remains poorly understood. Mst1/2 and their critical regulators RASSFs contain Salvador/RASSF1A/Hippo (SARAH) domains that can homo- and heterodimerize. Here, we report the crystal structures of human Mst2 alone and bound to RASSF5. Mst2 undergoes activation through transautophosphorylation at its activation loop, which requires SARAH-mediated homodimerization. RASSF5 disrupts Mst2 homodimer and blocks Mst2 autoactivation. Binding of RASSF5 to already activated Mst2, however, does not inhibit its kinase activity. Thus, RASSF5 can act as an inhibitor or a potential positive regulator of Mst2, depending on whether it binds to Mst2 before or after activation-loop phosphorylation. We propose that these temporally sensitive functions of RASSFs enable the Hippo pathway to respond to and integrate diverse cellular signals.