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J Biol Chem, Vol. 275, Issue 15, 11412-11417, April 14, 2000
From the Cartilage oligomeric matrix protein (COMP) is a
member of the thrombospondin family of extracellular matrix
glycoproteins. All members of the family contain a highly conserved
region of thrombospondin type 3 sequence repeats that bind calcium. A
mutation in COMP previously identified in a patient with
pseudoachondroplasia resulted in abnormal sequestration of COMP in
distinctive rER vesicles. The mutation, Asp-446
A Cartilage Oligomeric Matrix Protein Mutation Associated with
Pseudoachondroplasia Changes the Structural and Functional Properties
of the Type 3 Domain*
§,¶,, and¶
Research Department, Shriners Hospital for
Children, the § Department of Oral and Molecular Biology,
and the ¶ Department of Biochemistry and Molecular Biology, Oregon
Health Sciences University, Portland, Oregon, 97201
Asn, is located in
the type 3 repeats of the molecule. This region was expressed in a
mammalian culture with and without the mutation to study the structural or functional properties associated with the mutation. The biophysical parameters of the mutant peptide were compared with those of the wild
type and revealed the following difference: secondary structural analysis by circular dichroism showed more 
-helix content in the
wild-type peptides. The calcium binding properties of the two peptides
were significantly different; there were 17 calcium ions
bound/wild-type COMP3 peptide compared with 8/mutant peptide. In
addition, wild-type COMP3 had a higher affinity for calcium and bound
calcium more cooperatively. Calcium bound by the wild-type peptide was
reflected in a structural change as indicted by velocity sedimentation.
Thus, the effect of the COMP mutation appears to profoundly alter the
calcium binding properties and may account for the difference observed
in the structure of the type 3 domain. Furthermore, the highly
cooperative binding of calcium to COMP3 suggests that these type 3 sequence repeats form a single protein domain, the thrombospondin type
3 domain.
*
This work was supported by grants from Shriners Hospital for
Children (to H. P. B. and D. R. K.), the R. Blaine
Bramble Medical Research Foundation, the Fred Meyer Charitable Trust,
and by Grant AR45582 from the Department of Health and Human Services.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed. Tel.:
503-221-3433; Fax: 503-221-3451; E-mail: hpb@shcc.org.
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