LRP1 endocytosis is regulated by KIF13B through the interaction with hDLG1
Mills, Joslyn.
2018
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Abstract: KIF13B, a kinesin-3 family motor, was originally identified by
virtue of its biochemical interaction with human homolog of Drosophila discs large tumor
suppressor (hDLG1). Unlike its homolog KIF13A, the KIF13B contains a carboxyl-terminal
CAP-Gly domain. To investigate the specific functional role of the CAP-Gly domain in
KIF13B, and its possible compensation by KIF13A, we developed ... read moretwo mouse models. One mouse
model expresses a truncated form of KIF13B protein lacking only its CAP-Gly domain
(KIF13BΔCG), whereas the second model lacks the full-length KIF13A (KIF13A FLKO). Using
these mouse models, we show that the KIF13BΔCG mice exhibit relatively higher levels of
serum cholesterol consistent with the reduced uptake of [3H]CO-LDL in KIF13BΔCG mouse
embryo fibroblasts. In contrast, the serum level of factor VIII was not significantly
elevated in the KIF13BΔCG as compared to wild-type mice, suggesting that the CAP-Gly domain
of KIF13B selectively regulates Low density lipoprotein Related Protein 1-mediated
lipoprotein endocytosis. No elevation of either serum cholesterol or factor VIII was
observed in the KIF13A FLKO. Moreover, we found that the deletion of the CAP-Gly domain
caused subcellular mislocalization of truncated KIF13B with concomitant mislocalization of
LRP1. To further delineate the biochemical basis of the LRP1-KIF13B complex at the plasma
membrane, we discovered that the cytoplasmic domain of LRP1 interacts specifically with the
alternatively spliced I3 domain of hDLG1, which in turn recognizes the MBS domain of
KIF13B. Together, this study provides evidence for the biochemical basis of
LRP1-hDlg1-KIF13B complex formation, which regulates LRP1-mediated interactions with
implications in metabolism, cell polarity, and development.
Thesis (Ph.D.)--Tufts University, 2018.
Submitted to the Dept. of Cellular & Molecular Physiology.
Advisors: Laura Liscum, and Athar Chishti.
Committee: Peter Juo, Brent Cochran, and Ronald Dubreuil.
Keywords: Cellular biology, Biochemistry, and Molecular biology.read less - ID:
- wd376772q
- Component ID:
- tufts:26073
- To Cite:
- DCA Citation Guide EndNote
