Identification and characterization of a novel human matrix metalloproteinase with unique structural characteristics, chromosomal location, and tissue distribution

被引:167
作者
Pendas, AM
Knauper, V
Puente, XS
Llano, E
Mattei, MG
Apte, S
Murphy, G
LopezOtin, C
机构
[1] UNIV OVIEDO,FAC MED,DEPT BIOQUIM & BIOL MOL,E-33006 OVIEDO,SPAIN
[2] STRANGEWAYS RES LAB,DEPT CELL & MOL BIOL,CAMBRIDGE CB1 4RN,ENGLAND
[3] HOP ENFANTS LA TIMONE,INSERM U406,F-13385 MARSEILLE,FRANCE
[4] CLEVELAND CLIN FDN,DEPT BIOMED ENGN,CLEVELAND,OH 44195
关键词
D O I
10.1074/jbc.272.7.4281
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
We have cloned a novel member of the matrix metalloproteinase (MMP) family of proteins from a human liver cDNA library, The isolated cDNA contains an open reading frame coding for a polypeptide of 508 amino acids, which has been tentatively called MMP-19. This protein exhibits the domain structure characteristic of previously described MMPs, including a signal sequence, a prodomain with the cysteine residue essential for maintaining the latency of these enzymes, an activation locus with the zinc-binding site, and a COOH-terminal fragment with sequence similarity to hemopexin. However, it lacks a series of structural features distinctive of the diverse MMP subclasses, including the Asp, Tyr, and Gly residues located close to the zinc-binding site in collagenases, the fibronectin-like domain of gelatinases, the transmembrane domain of membrane-type (MT) MMPs, and the furin-activation sequence common to stromelysin-3 and MT-MMPs, In addition, the 9-residue insertion rich in hydrophobic amino acids present at the hinge region in stromelysins is replaced in MMP-19 by a longer insertion very rich in acidic residues. On the basis of these structural characteristics, we propose that MMP-19 does not belong to any of the previously defined MMP-subclasses and may represent the first member of a new MMP subfamily. Chromosomal location of the MMP-19 gene revealed that it maps to chromosome 12q14, which is also a unique location for any MMPs mapped to date. The cDNA encoding a full-length MMP-19 was expressed in Escherichia coli, and after purification and refolding, the recombinant protein was able to degrade synthetic substrates for MMPs. MMP-19 proteolytic activity was abolished by TIMP-2 and EDTA, thus providing additional evidence that the isolated cDNA codes for an authentic MMP. Northern blot analysis of polyadenylated RNAs isolated from a variety of human tissues revealed that MMP-19 is mainly expressed in placenta, lung, pancreas, ovary, spleen, and intestine, suggesting that it may play a specialized role in these tissues.
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收藏
页码:4281 / 4286
页数:6
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