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Ya Ha, PhD

Associate Professor of Pharmacology
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Contact Info

Pharmacology

PO Box 208066, 333 Cedar Street

New Haven, CT 06520-8066

United States

About

Titles

Associate Professor of Pharmacology

Appointments

Education & Training

Postdoctoral Fellow
Harvard University (2001)
PhD
University of Minnesota (1998)
BS
Nanjing University (1992)

Research

Overview

(1) Phosphatidylinositol phosphate kinase

There are three types of phosphatidylinositol phosphate (PIP) kinases that are homologous in amino acid sequence within their catalytic domains. The type I kinase PIP5K is responsible for the synthesis of the bulk of cellular PI(4,5)P2 from lipid substrate PI(4)P. The related type II kinase PIP4K and type III kinase PIKfyve differ in substrate binding specificity, recognizing PI(5)P and PI(3)P, respectively. Our recent work revealed two sequence segments within the catalytic domain that contribute to the kinase’s ability to distinguish these structurally similar lipids. Ongoing crystallographic work aims to provide the structural basis for this hypothesis.

High-throughput screening and structure-based design have yielded highly potent and selective inhibitors for the alpha and beta isoforms of type II kinase PIP4K. We currently use these chemical probes to unravel the complex functions of PIP4K, especially in energy metabolism. Recent genetic studies have revealed a unique dependence of p53-null tumor cells on PIP4Kalpha and PIP4Kbeta. Based on this, we are actively investigating the potential of using PIP4K inhibitors to kill tumor cells that harbor loss-of-function mutations in tumor suppressor p53.

(2) cis-prenyltransferase

Eukaryotic cis-prenyltransferase catalyzes the rate-limiting step in the synthesis of dolichol, glycosyl carrier lipids required for protein glycosylation. Different from the ancestral bacterial enzymes, it is composed of two protein subunits, a membrane-bound Nogo-B receptor (NgBR) subunit and a soluble dehydrodolichyl diphosphate synthase (DHDDS) subunit, and generates a range of long-chain lipid products. Mutations in either NgBR or DHDDS subunits have been found to cause human disease. A recent crystal structure of the NgBR/DHDDS heterodimeric complex has shed light on the composition of the enzyme’s active site and suggested how interactions with the membrane regulates the enzyme’s activity and influences isoprene product chain length, which we plan to further test with biochemical and biophysical experiments. Another interesting question under investigation is whether some disease-causing mutations, which usually reduce activity, could be rescued by small-molecule allosteric activators.

(3) Intramembrane protease

Intramembrane proteases are involved in many important pathways responsible for metabolic regulation and cell signaling. The X-ray structures of rhomboid protease and GxGD protease, both solved first in our laboratory, have revealed general architectural principles for these two membrane protein families, enabling us to ask specific questions about their unique biochemical mechanisms. One question concerns how the protease changes conformation during catalysis. Since the active site of the protease is filled with water, it needs to be closed initially to minimize unfavorable contact with lipid. How does transmembrane substrate, whose diffusion is restricted to the membrane plane, gain access to the active site? The crystal structures showed that the proteases have narrow transmembrane domains, suggesting that the lipid bilayer is constricted around the protein. Can this affect the presentation of buried cleavage sites to the protease? Finally, how does the protease achieve specificity? To study these questions, we apply a range of biochemical and biophysical techniques to the two protease systems described above. The knowledge generated from these studies has both conceptual and practical significance because many membrane proteases are potential targets for pharmacological intervention.

Medical Research Interests

Chemicals and Drugs; Crystallography, X-Ray; Membrane Proteins; Pharmacology

Public Health Interests

Aging; Cancer; Metabolism; Viruses

Research at a Glance

Yale Co-Authors

Frequent collaborators of Ya Ha's published research.

Publications

2021

2020

2016

2015

2011

2007

2006

2004

Get In Touch

Contacts

Academic Office Number
Lab Number
Office Fax Number
Mailing Address

Pharmacology

PO Box 208066, 333 Cedar Street

New Haven, CT 06520-8066

United States

Administrative Support

Locations

  • Sterling Hall of Medicine, B-Wing

    Academic Office

    333 Cedar Street, Ste SHM B345B

    New Haven, CT 06510