Selective intracellular retention of extracellular matrix proteins and chaperones associated with pseudoachondroplasia

Vranka, Janice A.; Mokashi, Asawari; Keene, Douglas R.; Tufa, Sara F.; Corson, Glen M.; Sussman, Michael D.; Horton, William A.; Maddox, Kerry; Sakai, Lynn Y.; Bächinger, Hans Peter

doi:10.1016/s0945-053x(01)00148-2

Cited by 76 publications

(79 citation statements)

References 47 publications

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“…COMP appears to mediate chondrocyte attachment via an integrin receptor (5), and several reports suggest that COMP may function to stabilize the articular cartilage ECM by specific cation-dependent interactions with matrix components, including collagen types II and IX, fibronectin, aggrecan, and matrilin-1, -3, and -4 (11,(52)(53)(54)(55). COMP has also been shown to associate with several chaperone proteins, including BiP, calreticulin, protein disulfide, ERp72, Grp94, HSP47, and calnexin, and it has been proposed that these associations facilitate the processing and transport of wild-type COMP in normal chondrocytes and inthe retention of mutant COMP in pseudoachondroplasia chondrocytes (56)(57)(58). In addition to the interactions between COMP and its protein partners, the five-stranded N-terminal domain of COMP forms a complex with vitamin DL-3, illustrating that COMP has storage function for hydrophobic compounds, including prominent cell-signaling molecules (59).…”

Section: Discussionmentioning

confidence: 99%

ADAMTS‐7: a metalloproteinase that directly binds to and degrades cartilage oligomeric matrix protein

Liu¹,

et al. 2006

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Degradative fragments of cartilage oligomeric matrix protein (COMP) have been observed in arthritic patients. The physiological enzyme(s) that degrade COMP, however, remain unknown. We performed a yeast two-hybrid screen (Y2H) to search for proteins that associate with COMP to identify an interaction partner that might degrade it. One screen using the epidermal growth factor (EGF) domain of COMP as bait led to the discovery of ADAMTS-7. Rat ADAMTS-7 is composed of 1595 amino acids, and this protein exhibits higher expression in the musculoskeletal tissues. COMP binds directly to ADAMTS-7 in vitro and in native articular cartilage. ADAMTS-7 selectively interacts with the EGF repeat domain but not with the other three functional domains of COMP, whereas the four C-terminal TSP motifs of ADAMTS-7 are required and sufficient for association with COMP. The recombinant catalytic domain and intact ADAMTS-7 are capable of digesting COMP in vitro. The enzymatic activity of ADAMTS-7 requires the presence of Zn 2+ and appropriate pH (7.5-9.5), and the concentration of ADAMTS-7 in cartilage and synovium of patients with rheumatoid arthritis is significantly increased as compared to normal cartilage and synovium. ADAMTS-7 is the first metalloproteinase found to bind directly to and degrade COMP.-Liu, C., Kong, W., Ilalov, K., Yu, S., Xu, K., Prazak, L., Fajardo, M., Sehgal, B., Di Cesare, P. E. ADAMTS-7: a metalloproteinase that directly binds to and degrades cartilage oligomeric matrix protein. The extracellular matrix (ECM) of cartilage consists of several types of collagens, proteoglycans, and other noncollagenous macromolecules, all of which interact to form a highly specialized connective tissue (1). Early extracellular cartilage matrix degeneration in arthritis is the result of the action of degradative enzymes. As the severity of arthritis progresses, the synthesis and secretion of matrix-degrading enzymes markedly increase (2). The control 1 These authors contributed equally to this work.

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Section: Discussionmentioning

confidence: 99%

ADAMTS‐7: a metalloproteinase that directly binds to and degrades cartilage oligomeric matrix protein

Liu¹,

et al. 2006

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“…16,[27][28][29]46 Secreted COMP observed in the circulation may play a role in storage and delivery of hydrophobic hormones and vitamins such as retinoic acid and vitamin D to target organs. 47 COMP is widely believed to play a structural role in the morphogenesis of cartilage with other matrix proteins.…”

Section: Discussionmentioning

confidence: 99%

“…16 -18 Other matrix proteins such as aggrecan and type IX, type XI, and type XII collagens are known to bind COMP and to accumulate together with mutated COMP. 18,26,29,46,48 Interaction of these proteins is assumed to require the intact calcium-binding domain of COMP. It is likely that this domain enables COMP to undergo appropriate protein folding and to bind with other matrix proteins to be secreted together.…”

Section: Discussionmentioning

confidence: 99%

“…[23][24][25] Extracellular matrix components, including aggrecan and type IX collagen, have been shown to be retained in these enlarged vesicles. [25][26][27][28][29] The retention appeared to be cell typespecific since COMP is secreted normally from patient tendon and ligament in vitro and patient chondrocytes cultured in monolayers. 27,28,30 However, it is still unclear how these mutations affect COMP trafficking and its pathway of secretion to cause disease phenotypes.…”

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confidence: 99%

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Mutation (D472Y) in the Type 3 Repeat Domain of Cartilage Oligomeric Matrix Protein Affects Its Early Vesicle Trafficking in Endoplasmic Reticulum and Induces Apoptosis

Hashimoto

Tomiyama

Yamano

et al. 2003

The American Journal of Pathology

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Cartilage oligomeric matrix protein (COMP) is a large pentameric extracellular glycoprotein found in cartilage, tendon, and synovium, and plays structural roles in cartilage as the fifth member of the thrombospondin family. Familial mutations in type 3 repeats of COMP are known to cause pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (EDM1). Although such mutations induce enlarged rough endoplasmic reticulum (rER) as a morphological change, the metabolic trafficking of mutated COMP remains unclear. In transfected COS7 cells, wild-type COMP was rapidly secreted into culture medium, while the great majority of COMP with the type 3 repeats mutation (D472Y) remained in the cells and a small portion of mutated COMP was secreted. This finding was followed up with a confocal study with an antibody specific to COMP, which demonstrated mutated COMP tightly associated with abnormally enlarged rER. Phosphorylated eIF2␣, an ER stress protein, was expressed as a pathological reaction in virtually all COS7 cells expressing mutated but not wild-type COMP. Moreover, COS7 cells expressing mutated COMP exhibited significantly more apoptotic reaction than those expressing wild-type COMP. Pathological accumulation of COMP in rER and apoptosis in COS7 cells that were induced by the mutation (D472Y) in COMP imply that COMP mutations play a role in the pathogenesis of PSACH. (Am J

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“…Over 100 signaturedomain mutations in THBS-5 (also known as cartilage oligomeric matrix protein or COMP) have been associated with the bone and joint diseases pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED) [35,36]. The endoplasmic reticula of chondrocytes from patients with PSACH are dilated and contain precipitated proteins consisting of THBS-5, type IX collagen, BiP, and calreticulin [37,38]. Phenocopies of the MED syndrome occur in patients with mutations of the α1, α2, or α3 chains of type IX collagen or matrilin-3 [39].…”

Section: The Signature Domain and Diseasementioning

confidence: 99%

Thrombospondins: from structure to therapeutics

Carlson

Lawler

Mosher

2008

Cell. Mol. Life Sci.

167

111

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Thrombospondins are large secreted, multi-modular, calcium-binding glycoproteins that have complex roles in mediating cellular processes. Determination of high-resolution structures of thrombospondins has revealed unique and interesting protein motifs. Here, we review this progress and discuss implications for function. By combining structures of modules from thrombospondins and related extracellular proteins it is now possible to prepare an overall model of the structure of thrombospondin-1 and thrombospondin-2 and discern features of other thrombospondins. (Part of a multi-author Review) KeywordsThrombospondin; extracellular protein structure; cartilage oligomeric matrix protein; calcium

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Selective intracellular retention of extracellular matrix proteins and chaperones associated with pseudoachondroplasia

Cited by 76 publications

References 47 publications

ADAMTS‐7: a metalloproteinase that directly binds to and degrades cartilage oligomeric matrix protein

ADAMTS‐7: a metalloproteinase that directly binds to and degrades cartilage oligomeric matrix protein

Mutation (D472Y) in the Type 3 Repeat Domain of Cartilage Oligomeric Matrix Protein Affects Its Early Vesicle Trafficking in Endoplasmic Reticulum and Induces Apoptosis

Thrombospondins: from structure to therapeutics

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