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Mutations in cartilage oligomeric matrix protein causing pseudoachondroplasia and multiple epiphyseal dysplasia affect binding of calcium and collagen I, II, and IX

Thur, Jochen; Rosenberg, Krisztina; Nitsche, D. Patric; Pihlajamaa, Tero; Ala-Kokko, Leena; Heinegård, Dick LU ; Paulsson, Mats and Maurer, Patrik (2001) In Journal of Biological Chemistry 276(9). p.6083-6092
Abstract
Mutations in type 3 repeats of cartilage oligomeric matrix protein (COMP) cause two skeletal dysplasias, pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED). We expressed recombinant wild-type COMP that showed structural and functional properties identical to COMP isolated from cartilage. A fragment encompassing the eight type 3 repeats binds 14 calcium ions with moderate affinity and high cooperativity and presumably forms one large disulfide-bonded folding unit. A recombinant PSACH mutant COMP in which Asp-469 was deleted (D469 Delta) and a MED mutant COMP in which Asp-361 was substituted by Tyr (D361Y) were both secreted into the cell culture medium of human cells. Circular dichroism spectroscopy revealed only small... (More)
Mutations in type 3 repeats of cartilage oligomeric matrix protein (COMP) cause two skeletal dysplasias, pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED). We expressed recombinant wild-type COMP that showed structural and functional properties identical to COMP isolated from cartilage. A fragment encompassing the eight type 3 repeats binds 14 calcium ions with moderate affinity and high cooperativity and presumably forms one large disulfide-bonded folding unit. A recombinant PSACH mutant COMP in which Asp-469 was deleted (D469 Delta) and a MED mutant COMP in which Asp-361 was substituted by Tyr (D361Y) were both secreted into the cell culture medium of human cells. Circular dichroism spectroscopy revealed only small changes in the secondary structures of D469 Delta and D361Y, demonstrating that the mutations do not dramatically affect the folding and stability of COMP. However, the local conformations of the type 3 repeats were disturbed, and the number of bound calcium ions was reduced to 10 and 8, respectively. In addition to collagen I and II, collagen IX also binds to COMP with high affinity. The PSACH and MED mutations reduce the binding to collagens I, II, and IX and result in an altered zinc dependence. These interactions may contribute to the development of the patient phenotypes and may explain why MED can also be caused by mutations in collagen IX genes. (Less)
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author
organization
publishing date
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Contribution to journal
publication status
published
subject
in
Journal of Biological Chemistry
volume
276
issue
9
pages
6083 - 6092
publisher
ASBMB
external identifiers
  • pmid:11084047
  • scopus:0035794206
ISSN
1083-351X
DOI
10.1074/jbc.M009512200
language
English
LU publication?
yes
id
7fc75491-e78d-49e8-847c-2c6f8c10841f (old id 1122719)
date added to LUP
2008-07-16 10:32:04
date last changed
2018-01-07 05:25:28
@article{7fc75491-e78d-49e8-847c-2c6f8c10841f,
  abstract     = {Mutations in type 3 repeats of cartilage oligomeric matrix protein (COMP) cause two skeletal dysplasias, pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED). We expressed recombinant wild-type COMP that showed structural and functional properties identical to COMP isolated from cartilage. A fragment encompassing the eight type 3 repeats binds 14 calcium ions with moderate affinity and high cooperativity and presumably forms one large disulfide-bonded folding unit. A recombinant PSACH mutant COMP in which Asp-469 was deleted (D469 Delta) and a MED mutant COMP in which Asp-361 was substituted by Tyr (D361Y) were both secreted into the cell culture medium of human cells. Circular dichroism spectroscopy revealed only small changes in the secondary structures of D469 Delta and D361Y, demonstrating that the mutations do not dramatically affect the folding and stability of COMP. However, the local conformations of the type 3 repeats were disturbed, and the number of bound calcium ions was reduced to 10 and 8, respectively. In addition to collagen I and II, collagen IX also binds to COMP with high affinity. The PSACH and MED mutations reduce the binding to collagens I, II, and IX and result in an altered zinc dependence. These interactions may contribute to the development of the patient phenotypes and may explain why MED can also be caused by mutations in collagen IX genes.},
  author       = {Thur, Jochen and Rosenberg, Krisztina and Nitsche, D. Patric and Pihlajamaa, Tero and Ala-Kokko, Leena and Heinegård, Dick and Paulsson, Mats and Maurer, Patrik},
  issn         = {1083-351X},
  language     = {eng},
  number       = {9},
  pages        = {6083--6092},
  publisher    = {ASBMB},
  series       = {Journal of Biological Chemistry},
  title        = {Mutations in cartilage oligomeric matrix protein causing pseudoachondroplasia and multiple epiphyseal dysplasia affect binding of calcium and collagen I, II, and IX},
  url          = {http://dx.doi.org/10.1074/jbc.M009512200},
  volume       = {276},
  year         = {2001},
}