Serine-Threonine Kinase Receptor-Associated Protein (STRAP) Regulates Translation of Type I Collagen mRNAs

Abstract

Type I collagen is the most abundant protein in the human body and is composed of two α1(I) and one α2(I) polypeptides which assemble into a triple helix. For the proper assembly of the collagen triple helix, the individual polypeptides must be translated in coordination. Here, we show that serine-threonine kinase receptor-associated protein (STRAP) is tethered to collagen mRNAs by interaction with LARP6. LARP6 is a protein which directly binds the 5′ stem-loop (5′SL) present in collagen α1(I) and α2(I) mRNAs, but it interacts with STRAP with its C-terminal domain, which is not involved in binding 5′SL. Being tethered to collagen mRNAs, STRAP prevents unrestricted translation, primarily that of collagen α2(I) mRNAs, by interacting with eukaryotic translation initiation factor 4A (eIF4A). In the absence of STRAP, more collagen α2(I) mRNA can be pulled down with eIF4A, and collagen α2(I) mRNA is unrestrictedly loaded onto the polysomes. This results in an imbalance of synthesis of α1(I) and α2(I) polypeptides, in hypermodifications of α1(I) polypeptide, and in inefficient assembly of the polypeptides into a collagen trimer and their secretion as monomers. These defects can be partially restored by supplementing STRAP. Thus, we discovered STRAP as a novel regulator of the coordinated translation of collagen mRNAs.

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.00195-13.

ACKNOWLEDGMENTS

Special thanks go to P. Soriano for kindly providing us with WT and STRAP^−/−MEFs, to N. Sonenberg for generously providing eIF4A- and eIF4E-containing plasmids, to Y. Kato for appreciated assistance with qRT-PCR, to V. Marin for technical support with 2D SDS electrophoresis, to A. Challa, R. Rizkalah, L. Stefanovic, and Y. Zhang for laboratory help and valuable discussions of the manuscript, and to T. Megraw for valuable comments on the manuscript.

This work was supported by National Institutes of Health grant 2R01DK059466-07A2 to B.S.