PMID- 12237470
OWN - NLM
STAT- MEDLINE
DCOM- 20030311
LR  - 20181113
IS  - 0961-8368 (Print)
IS  - 1469-896X (Electronic)
IS  - 0961-8368 (Linking)
VI  - 11
IP  - 10
DP  - 2002 Oct
TI  - Mapping and characterization of the functional epitopes of tissue inhibitor of 
      metalloproteinases (TIMP)-3 using TIMP-1 as the scaffold: a new frontier in TIMP 
      engineering.
PG  - 2493-503
AB  - Tumor necrosis factor-alpha (TNF-alpha) converting enzyme (TACE/ADAM-17) is 
      responsible for the release of TNF-alpha, a potent proinflammatory cytokine 
      associated with many chronic debilitating diseases such as rheumatoid arthritis. 
      Among the four variants of mammalian tissue inhibitor of metalloproteinases 
      (TIMP-1 to -4), TACE is specifically inhibited by TIMP-3. We set out to delineate 
      the basis for this specificity by examining the solvent accessibility of every 
      epitope on the surface of a model of the truncated N-terminal domain form of 
      TIMP-3 (N-TIMP-3) in a hypothetical complex with the crystal structure of TACE. 
      The epitopes suspected of interacting with TACE were systematically transplanted 
      onto N-TIMP-1. We succeeded in transforming N-TIMP-1 into an active inhibitor for 
      TACE (K(i)(app) 15 nM) with the incorporation of Ser4, Leu67, Arg84, and the 
      TIMP-3 AB-loop. The combined effects of these epitopes are additive. 
      Unexpectedly, introduction of "super-N-TIMP-3" epitopes, defined in our previous 
      work, only impaired the affinity of N-TIMP-1 for TACE. Our mutagenesis results 
      indicate that TIMP-3-TACE interaction is a delicate process that requires highly 
      refined surface topography and flexibility from both parties. Most importantly, 
      our findings confirm that the individual characteristics of TIMP could be 
      transplanted from one variant to another.
FAU - Lee, Meng-Huee
AU  - Lee MH
AD  - School of Biological Sciences, University of East Anglia, Norwich NR4 7TJ, UK.
FAU - Maskos, Klaus
AU  - Maskos K
FAU - Knauper, Vera
AU  - Knauper V
FAU - Dodds, Philippa
AU  - Dodds P
FAU - Murphy, Gillian
AU  - Murphy G
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Protein Sci
JT  - Protein science : a publication of the Protein Society
JID - 9211750
RN  - 0 (Epitopes)
RN  - 0 (Tissue Inhibitor of Metalloproteinase-1)
RN  - 0 (Tissue Inhibitor of Metalloproteinase-3)
RN  - EC 3.4.24.- (ADAM Proteins)
RN  - EC 3.4.24.- (Metalloendopeptidases)
RN  - EC 3.4.24.86 (ADAM17 Protein)
RN  - EC 3.4.24.86 (ADAM17 protein, human)
SB  - IM
MH  - ADAM Proteins
MH  - ADAM17 Protein
MH  - Amino Acid Sequence
MH  - *Epitope Mapping
MH  - Epitopes/*immunology
MH  - Humans
MH  - Metalloendopeptidases/immunology
MH  - Models, Molecular
MH  - Molecular Sequence Data
MH  - Mutation
MH  - Protein Folding
MH  - Sequence Alignment
MH  - Tissue Inhibitor of Metalloproteinase-1/*immunology
MH  - Tissue Inhibitor of Metalloproteinase-3/genetics/*immunology
PMC - PMC2373703
EDAT- 2002/09/19 10:00
MHDA- 2003/03/12 04:00
PMCR- 2003/10/01
CRDT- 2002/09/19 10:00
PHST- 2002/09/19 10:00 [pubmed]
PHST- 2003/03/12 04:00 [medline]
PHST- 2002/09/19 10:00 [entrez]
PHST- 2003/10/01 00:00 [pmc-release]
AID - 0112493 [pii]
AID - 10.1110/ps.0216202 [doi]
PST - ppublish
SO  - Protein Sci. 2002 Oct;11(10):2493-503. doi: 10.1110/ps.0216202.