4oli

From Proteopedia

The pseudokinase/kinase protein from JAK-family member TYK2

PDB ID 4oli

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Structural highlights

4oli is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.8Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

TYK2_HUMAN Mendelian susceptibility to mycobacterial diseases;Autosomal recessive hyper IgE syndrome. Defects in TYK2 are the cause of protein-tyrosine kinase 2 deficiency (TYK2 deficiency) [MIM:611521; also known as autosomal recessive hyper-IgE syndrome (HIES) with atypical mycobacteriosis. TYK2 deficiency consists of a primary immunodeficiency characterized by recurrent skin abscesses, pneumonia, and highly elevated serum IgE.

Function

TYK2_HUMAN Probably involved in intracellular signal transduction by being involved in the initiation of type I IFN signaling. Phosphorylates the interferon-alpha/beta receptor alpha chain.^[1]

Publication Abstract from PubMed

Janus kinases (JAKs) are receptor-associated multidomain tyrosine kinases that act downstream of many cytokines and interferons. JAK kinase activity is regulated by the adjacent pseudokinase domain via an unknown mechanism. Here, we report the 2.8-A structure of the two-domain pseudokinase-kinase module from the JAK family member TYK2 in its autoinhibited form. We find that the pseudokinase and kinase interact near the kinase active site and that most reported mutations in cancer-associated JAK alleles cluster in or near this interface. Mutation of residues near the TYK2 interface that are analogous to those in cancer-associated JAK alleles, including the V617F and "exon 12" JAK2 mutations, results in increased kinase activity in vitro. These data indicate that JAK pseudokinases are autoinhibitory domains that hold the kinase domain inactive until receptor dimerization stimulates transition to an active state.

Structure of the pseudokinase-kinase domains from protein kinase TYK2 reveals a mechanism for Janus kinase (JAK) autoinhibition.,Lupardus PJ, Ultsch M, Wallweber H, Bir Kohli P, Johnson AR, Eigenbrot C Proc Natl Acad Sci U S A. 2014 May 19. pii: 201401180. PMID:24843152^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Colamonici O, Yan H, Domanski P, Handa R, Smalley D, Mullersman J, Witte M, Krishnan K, Krolewski J. Direct binding to and tyrosine phosphorylation of the alpha subunit of the type I interferon receptor by p135tyk2 tyrosine kinase. Mol Cell Biol. 1994 Dec;14(12):8133-42. PMID:7526154
↑ Lupardus PJ, Ultsch M, Wallweber H, Bir Kohli P, Johnson AR, Eigenbrot C. Structure of the pseudokinase-kinase domains from protein kinase TYK2 reveals a mechanism for Janus kinase (JAK) autoinhibition. Proc Natl Acad Sci U S A. 2014 May 19. pii: 201401180. PMID:24843152 doi:http://dx.doi.org/10.1073/pnas.1401180111