RT Journal Article
SR Electronic
T1 Allosteric feed-forward activation of AP-2 <em>via</em> FCHO-BMP2K axis promotes clathrin-mediated endocytosis
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 870899
DO 10.1101/870899
A1 Shikha T. Ramesh
A1 Kolaparamba V. Navyasree
A1 Anjitha B. Ashok
A1 Nishada Qathoon
A1 Suryasikha Mohanty
A1 Rajeeb K. Swain
A1 Perunthottathu K. Umasankar
YR 2019
UL http://biorxiv.org/content/early/2019/12/10/870899.abstract
AB Spatio-temporal regulation of central adaptor complex, AP-2 is pivotal for clathrin-mediated endocytosis (CME). We recently discovered that FCHO proteins trigger clathrin-coated pit (CCP) formation by allosterically activating AP-2 on plasma membrane (Umasankar et al., 2014). Here, we demonstrate that this activation promotes AP-2 phosphorylation via recruitment and stabilization of BMP-2 inducible kinase (BMP2K), a bona fide AP-2 kinase leading to CCP maturation. Accordingly, BMP2K mislocalizes and degrades in FCHO knockout/ AP-2 depleted cells. Functional inactivation of kinase impairs AP-2 phosphorylation leading to altered lattice morphology and CME phenotypes reminiscent of CCP maturation defects. Reexpression of FCHO rescues AP-2 phosphorylation defects in FCHO knockout cells implying membrane activation of AP-2 is a prerequisite for kinase function. Furthermore, gain- and loss-of function phenotypes of FCHO and BMP2K are analogous and mirror altered AP-2 functions during zebrafish embryogenesis. Together, our findings reveal an in vivo allosteric feed-forward axis for operation of CME.