Protein kinase C

 

Atypical protein kinase C iota (aPKC iota) from Homo sapiens catalyses the phosphorylation of a protein by hydrolysing ATP to ADP. aPKC iota can phosphorylate a number of different proteins, including interleukin receptor-associated kinase. aPKCs play critical roles in signalling pathways that control cell growth, differentiation and survival. Therefore they constitute targets for the development of novel therapeutics against cancer, for aPKC iota, specifically colon cancer and chronic myelogenous leukemia.

 

Reference Protein and Structure

Sequence
P41743 UniProt (2.7.11.13) IPR012233 (Sequence Homologues) (PDB Homologues)
Biological species
Homo sapiens (Human) Uniprot
PDB
1zrz - Crystal Structure of the Catalytic Domain of Atypical Protein Kinase C-iota (3.0 Å) PDBe PDBsum 1zrz
Catalytic CATH Domains
1.10.510.10 CATHdb (see all for 1zrz)
Click To Show Structure

Enzyme Reaction (EC:2.7.11.13)

L-serine residue
CHEBI:29999ChEBI
+
ATP(4-)
CHEBI:30616ChEBI
→
O-phospho-L-serine(2-) residue
CHEBI:83421ChEBI
+
ADP(3-)
CHEBI:456216ChEBI
+
hydron
CHEBI:15378ChEBI
Alternative enzyme names: Calcium-dependent protein kinase C, Calcium-independent protein kinase C, Calcium/phospholipid dependent protein kinase, CPKC-alpha, CPKC-beta, CPKC-gamma, NPKC-delta, NPKC-epsilon, NPKC-eta, NPKC-theta, PKC, PKC-alpha, PKC-beta, PKC-gamma, PKC-delta, PKC-epsilon, PKC-zeta, Pkc1p, Protein kinase C-epsilon, STK24, NPKC, CPKC,

Enzyme Mechanism

Introduction

Asp 369 acts as a base by abstracting a proton from the phosphoacceptor, activating it for nucleophilic attack on the gamma phosphorus atom of ATP. Asp 369 is stabilised by a hydrogen bond to its main chain carbonyl from Asn 374. The reaction goes through a pentavalent transition state which is stabilised by Lys 371. The proton picked up by Asp 369 is then probably donated to the leaving group ADP.

Catalytic Residues Roles

UniProt PDB* (1zrz)
Asp378 Asp369(146)A Acts as a general base, deprotonating the phosphoacceptor, activating it for nucleophilic attack on the gamma phosphate of ATP. proton shuttle (general acid/base)
Lys380 Lys371(148)A Stabilises the transition state by hydrogen bonding to the gamma phosphate group of ATP. electrostatic stabiliser
Asn383 Asn374(151)A Stabilises Asp 369 by hydrogen bonding to its main chain carboxylate. electrostatic stabiliser
*PDB label guide - RESx(y)B(C) - RES: Residue Name; x: Residue ID in PDB file; y: Residue ID in PDB sequence if different from PDB file; B: PDB Chain; C: Biological Assembly Chain if different from PDB. If label is "Not Found" it means this residue is not found in the reference PDB.

Chemical Components

References

  1. Messerschmidt A et al. (2005), J Mol Biol, 352, 918-931. Crystal Structure of the Catalytic Domain of Human Atypical Protein Kinase C-iota Reveals Interaction Mode of Phosphorylation Site in Turn Motif. DOI:10.1016/j.jmb.2005.07.060. PMID:16125198.

Step 1.

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Catalytic Residues Roles

Residue Roles
Asn374(151)A electrostatic stabiliser
Asp369(146)A proton shuttle (general acid/base)
Lys371(148)A electrostatic stabiliser

Chemical Components

Step 1.

Contributors

Ellie Wright, Gemma L. Holliday, Morwenna Hall