4isl
Crystal Structure of the inactive Matriptase in complex with its inhibitor HAI-1Crystal Structure of the inactive Matriptase in complex with its inhibitor HAI-1
Structural highlights
Disease[ST14_HUMAN] Defects in ST14 are a cause of ichthyosis autosomal recessive with hypotrichosis (ARIH) [MIM:610765]. ARIH is a skin disorder characterized by congenital ichthyosis associated with the presence of less than the normal amount of hair.[1] Function[SPIT1_HUMAN] Inhibitor of HGF activator. Also acts as an inhibitor of matriptase (ST14). [ST14_HUMAN] Degrades extracellular matrix. Proposed to play a role in breast cancer invasion and metastasis. Exhibits trypsin-like activity as defined by cleavage of synthetic substrates with Arg or Lys as the P1 site. Publication Abstract from PubMedMatriptase, a type II trans-membrane serine protease of the S1 trypsin-like family, is expressed on the surface of nearly all normal human epithelium and found in biological fluid-like human milk. Matriptase overexpression has been implicated in tumor progression in certain epithelium-derived cancer cells. Matriptase is tightly regulated by its cognate inhibitor hepatocyte growth factor activator inhibitor-1 (HAI-1). It has been demonstrated that the Kunitz domain I (KD1) but not Kunitz domain II (KD2) of HAI-1 is responsible for the inhibitory activity of HAI-1 against matriptase. To investigate the molecular basis of inhibition of matriptase by HAI-1, we solved several crystal structures of matriptase serine protease domain in complex with the fragments of HAI-1. Based on these structures, we found that the binding of KD1 was different from previously predicted binding mode. The P3 arginine residue occupies the S3 specificity pocket of matriptase, but not the S4 pocket as in the cases of hepatocyte growth factor activator.HAI-1 KD1 and matriptase.sunflower trypsin inhibitor-1 complexes. The long 60-loop of matriptase makes direct contact with HAI-1 but remains flexible even in the complexes, and its apex does not bind with KD1 tightly. The interactions between this unique 60-loop and KD1 may provide an opportunity to increase the specificity and inhibitory activity of KD1 for matriptase. Furthermore, comparison between KD1 and a homology model of HAI-1 KD2 rationalizes the structural basis of why KD1 but not KD2 is responsible for the inhibitory activity of HAI-1 against matriptase. Crystal structures of matriptase in complex with its inhibitor hepatocyte growth factor activator inhibitor-1.,Zhao B, Yuan C, Li R, Qu D, Huang M, Ngo JC J Biol Chem. 2013 Apr 19;288(16):11155-64. doi: 10.1074/jbc.M113.454611. Epub, 2013 Feb 26. PMID:23443661[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
|
| ||||||||||||||||||||||