| First Author | Mills J | Year | 2019 |
| Journal | Biochim Biophys Acta Mol Cell Res | Volume | 1866 |
| Issue | 12 | Pages | 118552 |
| PubMed ID | 31487503 | Mgi Jnum | J:282570 |
| Mgi Id | MGI:6379118 | Doi | 10.1016/j.bbamcr.2019.118552 |
| Citation | Mills J, et al. (2019) LDL receptor related protein 1 requires the I3 domain of discs-large homolog 1/DLG1 for interaction with the kinesin motor protein KIF13B. Biochim Biophys Acta Mol Cell Res 1866(12):118552 |
| abstractText | KIF13B, a kinesin-3 family motor, was originally identified as GAKIN due to its biochemical interaction with human homolog of Drosophila discs-large tumor suppressor (hDLG1). Unlike its homolog KIF13A, KIF13B contains a carboxyl-terminal CAP-Gly domain. To investigate the function of the CAP-Gly domain, we developed a mouse model that expresses a truncated form of KIF13B protein lacking its CAP-Gly domain (KIF13BDeltaCG), whereas a second mouse model lacks the full-length KIF13A. Here we show that the KIF13BDeltaCG mice exhibit relatively higher serum cholesterol consistent with the reduced uptake of [(3)H]CO-LDL in KIF13BDeltaCG mouse embryo fibroblasts. The plasma level of factor VIII was not significantly elevated in the KIF13BDeltaCG mice, suggesting that the CAP-Gly domain region of KIF13B selectively regulates LRP1-mediated lipoprotein endocytosis. No elevation of either serum cholesterol or plasma factor VIII was observed in the full length KIF13A null mouse model. The deletion of the CAP-Gly domain region caused subcellular mislocalization of truncated KIF13B concomitant with the mislocalization of LRP1. Mechanistically, the cytoplasmic domain of LRP1 interacts specifically with the alternatively spliced I3 domain of DLG1, which complexes with KIF13B via their GUK-MBS domains, respectively. Importantly, double mutant mice generated by crossing KIF13A null and KIF13BDeltaCG mice suffer from perinatal lethality showing potential craniofacial defects. Together, this study provides first evidence that the carboxyl-terminal region of KIF13B containing the CAP-Gly domain is important for the LRP1-DLG1-KIF13B complex formation with implications in the regulation of metabolism, cell polarity, and development. |
