CRIM1 regulates the rate of processing and delivery of bone morphogenetic proteins to the cell surface.
The Crim1 gene is predicted to encode a transmembrane protein containing six von Willebrand-like cysteine-rich repeats (CRRs) similar to those in the BMP-binding antagonist Chordin (Chrd). In this study, we verify that CRIM1 is a glycosylated, Type I transmembrane protein and demonstrate that the extracellular CRR-containing domain can also be secreted, presumably via processing at the membrane. We have previously demonstrated Crim1 expression at sites consistent with an interaction with bone morphogenetic proteins (BMPs). Here we show that CRIM1 can interact with both BMP4 and BMP7 via the CRR-containing portion of the protein and in so doing acts as an antagonist in three ways. CRIM1 binding of BMP4 and -7 occurs when these proteins are co-expressed within the Golgi compartment of the cell and leads to (i) a reduction in the production and processing of preprotein to mature BMP, (ii) tethering of pre-BMP to the cell surface, and (iii) an effective reduction in the secretion of mature BMP. Functional antagonism was verified by examining the effect of co-expression of CRIM1 and BMP4 on metanephric explant culture. The presence of CRIM1 reduced the effective BMP4 concentration of the media, thereby acting as a BMP4 antagonist. Hence, CRIM1 modulates BMP activity by affecting its processing and delivery to the cell surface.
Wilkinson
Lorine
L
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.
Kolle
Gabriel
G
Wen
Daying
D
Piper
Michael
M
Scott
Julie
J
Little
Melissa
M
D000818:Animals; D001665:Binding Sites; D019921:Biotinylation; D015153:Blotting, Western; D055415:Bone Morphogenetic Protein 4; D055419:Bone Morphogenetic Protein 7; D052004:Bone Morphogenetic Protein Receptors; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D019556:COS Cells; D002462:Cell Membrane / Q000378:metabolism*; D002478:Cells, Cultured; D005822:Genetic Vectors; D006031:Glycosylation; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D008856:Microscopy, Fluorescence; D008957:Models, Genetic; D009687:Nuclear Proteins / Q000378:metabolism* / Q000502:physiology*; D011233:Precipitin Tests; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D011506:Proteins; D013347:Subcellular Fractions / Q000378:metabolism; D014162:Transfection; D016212:Transforming Growth Factor beta
C525809:BMP4 protein, human; C525819:BMP7 protein, human; C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; C486175:CRIM1 protein, human; D008565:Membrane Proteins; D009687:Nuclear Proteins; D011506:Proteins; D016212:Transforming Growth Factor beta; C074370:cysteine-rich protein, mammalian; D052004:Bone Morphogenetic Protein Receptors