PMID- 10229672
OWN - NLM
STAT- MEDLINE
DCOM- 19990630
LR  - 20181113
IS  - 0264-6021 (Print)
IS  - 0264-6021 (Linking)
VI  - 340 ( Pt 1)
DP  - 1999 May 15
TI  - Fibrillin degradation by matrix metalloproteinases: implications for connective
      tissue remodelling.
PG  - 171-81
AB  - Fibrillin is the principal structural component of the 10-12 nm diameter elastic 
      microfibrils of the extracellular matrix. We have previously shown that both
      fibrillin molecules and assembled microfibrils are susceptible to degradation by 
      serine proteases. In this study, we have investigated the potential catabolic
      effects of six matrix metalloproteinases (MMP-2, MMP-3, MMP-9, MMP-12, MMP-13 and
      MMP-14) on fibrillin molecules and on intact fibrillin-rich microfibrils isolated
      from ciliary zonules. Using newly synthesized recombinant fibrillin molecules,
      major cleavage sites within fibrillin-1 were identified. In particular, the six
      different MMPs generated a major degradation product of approximately 45 kDa from
      the N-terminal region of the molecule, whereas treatment of truncated,
      unprocessed and furin-processed C-termini also generated large degradation
      products. Introduction of a single ectopia lentis-causing amino acid substitution
      (E2447K; one-letter symbols for amino acids) in a calcium-binding epidermal
      growth factor-like domain, predicted to disrupt calcium binding, markedly altered
      the pattern of C-terminal fibrillin-1 degradation. However, the fragmentation
      pattern of a mutant fibrillin-1 with a comparable E-->K substitution in an
      upstream calcium-binding epidermal growth factor-like domain was
      indistinguishable from wild-type molecules. Ultrastructural examination
      highlighted that fibrillin-rich microfibrils isolated from ciliary zonules were
      grossly disrupted by MMPs. This is the first demonstration that fibrillin
      molecules and fibrillin-rich microfibrils are degraded by MMPs and that certain
      amino acid substitutions change the fragmentation patterns. These studies have
      important implications for physiological and pathological fibrillin catabolism
      and for loss of connective tissue elasticity in ageing and disease.
FAU - Ashworth, J L
AU  - Ashworth JL
AD  - Wellcome Trust Centre for Cell-Matrix Research, School of Biological Sciences,
      University of Manchester, 2.205 Stopford Building, Oxford Road, Manchester M13
      9PT, UK.
FAU - Murphy, G
AU  - Murphy G
FAU - Rock, M J
AU  - Rock MJ
FAU - Sherratt, M J
AU  - Sherratt MJ
FAU - Shapiro, S D
AU  - Shapiro SD
FAU - Shuttleworth, C A
AU  - Shuttleworth CA
FAU - Kielty, C M
AU  - Kielty CM
LA  - eng
GR  - Wellcome Trust/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Biochem J
JT  - The Biochemical journal
JID - 2984726R
RN  - 0 (Extracellular Matrix Proteins)
RN  - 0 (FBN1 protein, human)
RN  - 0 (Fibrillin-1)
RN  - 0 (Fibrillins)
RN  - 0 (Microfilament Proteins)
RN  - 0 (Peptide Fragments)
RN  - 0 (Polymers)
RN  - 0 (Recombinant Proteins)
RN  - 9DLQ4CIU6V (Proline)
RN  - EC 3.4.24.- (Metalloendopeptidases)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Aging
MH  - Amino Acid Substitution
MH  - Binding Sites
MH  - Calcium/metabolism
MH  - Connective Tissue/*metabolism
MH  - Ectopia Lentis/genetics
MH  - Endoplasmic Reticulum/metabolism
MH  - Exons/genetics
MH  - Extracellular Matrix Proteins/biosynthesis/genetics/metabolism/ultrastructure
MH  - Fibrillin-1
MH  - Fibrillins
MH  - Humans
MH  - Metalloendopeptidases/*metabolism
MH  - Microfilament Proteins/biosynthesis/genetics/*metabolism/ultrastructure
MH  - Microscopy, Electron
MH  - Molecular Weight
MH  - Peptide Fragments/genetics/metabolism/ultrastructure
MH  - Polymers/metabolism
MH  - Proline/genetics/metabolism
MH  - Protein Processing, Post-Translational
MH  - Recombinant Proteins/biosynthesis/metabolism/ultrastructure
PMC - PMC1220235
EDAT- 1999/05/07 00:00
MHDA- 1999/05/07 00:01
CRDT- 1999/05/07 00:00
PHST- 1999/05/07 00:00 [pubmed]
PHST- 1999/05/07 00:01 [medline]
PHST- 1999/05/07 00:00 [entrez]
PST - ppublish
SO  - Biochem J. 1999 May 15;340 ( Pt 1):171-81.