Dissertation/Thesis Abstract

Mechanism of substrate specificity and insights into activation of phosphatidylinositol phosphate kinases
by Muftuoglu, Yagmur, Ph.D., Yale University, 2016, 111; 10584957
Abstract (Summary)

The phosphatidylinositol phosphate kinase family of enzymes is primarily responsible for converting singly phosphorylated phosphatidylinositol derivatives to phosphatidylinositol bisphosphates. As such, these kinases are central to many signaling and membrane trafficking processes in the eukaryotic cell. The three types of phosphatidylinositol phosphate kinases are homologous in sequence but differ in catalytic activities and biological functions. Type I and Type II kinases generate phosphatidylinositol 4,5-bisphosphate from phosphatidylinositol 4-phosphate and phosphatidylinositol 5-phosphate, respectively, whereas the Type III kinase produces phosphatidylinositol 3,5-bisphosphate from phosphatidylinositol 3-phosphate. Based on crystallographic analysis of the zebrafish Type I kinase PIP5Kα, we identified a subdomain unique to the kinase family that serves to recognize the monophosphate on the substrate. Our data indicate that the complex pattern of substrate recognition and phosphorylation results from the interplay between the monophosphate binding site and the specificity loop: the specificity loop functions to recognize different orientations of the inositol ring, whereas motifs flanking the phosphate binding Arg-244 determine whether phosphatidylinositol 3-phosphate is exclusively bound and phosphorylated at the 5-position. This work provides a thorough picture of how phosphatidylinositol phosphate kinases achieve their exquisite substrate specificity. In addition, the data presented here offers insights into activation of the Type I kinase, PIP5K, opening up a number of additional research questions yet to be addressed in this field.

Indexing (document details)
Advisor: Ha, Ya
Commitee:
School: Yale University
School Location: United States -- Connecticut
Source: DAI-B 78/07(E), Dissertation Abstracts International
Source Type: DISSERTATION
Subjects: Pharmacology, Biomedical engineering, Biophysics
Keywords: Crystallography, Lipid Kinase, Phosphatidylinositol Phosphates, Protein Engineering, Substrate Specificity
Publication Number: 10584957
ISBN: 9781369635423
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