Ya Ha, PhD
Associate Professor of PharmacologyCards
Appointments
Contact Info
Pharmacology
PO Box 208066, 333 Cedar Street
New Haven, CT 06520-8066
United States
About
Titles
Associate Professor of Pharmacology
Appointments
Pharmacology
Associate Professor TenurePrimary
Other Departments & Organizations
- Biochemistry, Quantitative Biology, Biophysics and Structural Biology (BQBS)
- Developmental Therapeutics
- Macromolecular X-Ray Crystallography
- Molecular Medicine, Pharmacology, and Physiology
- Pharmacology
- Primary Faculty
- Yale Cancer Center
- Yale Combined Program in the Biological and Biomedical Sciences (BBS)
- Yale Ventures
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 Subject Headings (MeSH)
Research at a Glance
Yale Co-Authors
Publications Timeline
Research Interests
Kariona Grabinska, PhD
Crystallography, X-Ray
Membrane Proteins
Publications
2021
Pharmacological inhibition of PI5P4Kα/β disrupts cell energy metabolism and selectively kills p53-null tumor cells
Chen S, Tjin C, Gao X, Xue Y, Jiao H, Zhang R, Wu M, He Z, Ellman J, Ha Y. Pharmacological inhibition of PI5P4Kα/β disrupts cell energy metabolism and selectively kills p53-null tumor cells. Proceedings Of The National Academy Of Sciences Of The United States Of America 2021, 118: e2002486118. PMID: 34001596, PMCID: PMC8166193, DOI: 10.1073/pnas.2002486118.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsMeSH KeywordsAMP-Activated Protein Kinase KinasesAnimalsEnergy MetabolismHumansInsulinInsulin Receptor Substrate ProteinsMechanistic Target of Rapamycin Complex 1MiceMuscle Fibers, SkeletalNeoplasmsPhosphorylationPhosphotransferases (Alcohol Group Acceptor)Ribosomal Protein S6 Kinases, 70-kDaSignal TransductionSmall Molecule LibrariesTumor Suppressor Protein p53ConceptsP53-null tumor cellsMost human cancer cellsCell energy homeostasisCell energy metabolismTumor suppressor genePI5P4KHuman cancer cellsGenetic experimentsDifferentiated myotubesAMPK activationStructural basisKinase activityEnergy stressMetabolic regulationSuppressor geneFunction mutationsLate-onset tumorsSubstrate loopP53 tumor suppressor geneChemical probesPI3KCell typesExquisite specificityEnergy metabolismTumor cells
2020
Structural elucidation of the cis-prenyltransferase NgBR/DHDDS complex reveals insights in regulation of protein glycosylation
Edani BH, Grabińska KA, Zhang R, Park EJ, Siciliano B, Surmacz L, Ha Y, Sessa WC. Structural elucidation of the cis-prenyltransferase NgBR/DHDDS complex reveals insights in regulation of protein glycosylation. Proceedings Of The National Academy Of Sciences Of The United States Of America 2020, 117: 20794-20802. PMID: 32817466, PMCID: PMC7456142, DOI: 10.1073/pnas.2008381117.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsActive site tunnelProtein glycosylationAtomic resolution structuresGlycosyl carrier lipidsΑ3 helixEnzyme active sitePTase activityResolution structureActive siteEndoplasmic reticulumHomodimeric formCarrier lipidRate-limiting stepGlycosylationCrystal structureDHDDSStructural elucidationPTaseIsoprene chainPrenyltransferaseUnique insightsComplexesUnfavorable stateNgBRHomodimeric
2016
Mechanism of substrate specificity of phosphatidylinositol phosphate kinases
Muftuoglu Y, Xue Y, Gao X, Wu D, Ha Y. Mechanism of substrate specificity of phosphatidylinositol phosphate kinases. Proceedings Of The National Academy Of Sciences Of The United States Of America 2016, 113: 8711-8716. PMID: 27439870, PMCID: PMC4978281, DOI: 10.1073/pnas.1522112113.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsPhosphatidylinositol phosphate kinaseKinase familySubstrate specificityPhosphate kinasePhosphatidylinositol phosphate kinase (PIPK) familyZebrafish type IMembrane trafficking processesExquisite substrate specificityType III kinaseEukaryotic cellsInositol ringPhosphorylation resultsSubstrate recognitionTrafficking processesSpecificity loopPhosphatidylinositol derivativesBiological functionsPhosphatidylinositol 4PhosphatidylinositolKinaseStructural motifsType IBisphosphateLoop functionsComplex patterns
2015
Resolution of structure of PIP5K1A reveals molecular mechanism for its regulation by dimerization and dishevelled
Hu J, Yuan Q, Kang X, Qin Y, Li L, Ha Y, Wu D. Resolution of structure of PIP5K1A reveals molecular mechanism for its regulation by dimerization and dishevelled. Nature Communications 2015, 6: 8205. PMID: 26365782, PMCID: PMC4570271, DOI: 10.1038/ncomms9205.Peer-Reviewed Original ResearchCitationsMeSH Keywords and ConceptsMeSH KeywordsAdaptor Proteins, Signal TransducingAnimalsBinding SitesCalorimetryCatalytic DomainCircular DichroismCrystallizationCrystallography, X-RayDimerizationDishevelled ProteinsHEK293 CellsHumansPhosphatidylinositol 4,5-DiphosphatePhosphatidylinositol PhosphatesPhosphoproteinsPhosphorylationPhosphotransferases (Alcohol Group Acceptor)Protein Structure, TertiaryZebrafishConceptsSubstrate-binding siteLipid kinasesDIX domainCellular functionsCatalytic domainPhosphate kinaseÅ resolutionMutagenesis studiesRegulatory mechanismsMolecular mechanismsCatalytic activityPIP5K1AHead groupsCrystal structureSide dimerKinaseWntStructural informationRegulationDimerizationMoleculesResolution of structuresImportant rolePhosphatidylinositolType I
2011
Crystal structure of amyloid precursor-like protein 1 and heparin complex suggests a dual role of heparin in E2 dimerization
Xue Y, Lee S, Ha Y. Crystal structure of amyloid precursor-like protein 1 and heparin complex suggests a dual role of heparin in E2 dimerization. Proceedings Of The National Academy Of Sciences Of The United States Of America 2011, 108: 16229-16234. PMID: 21930949, PMCID: PMC3182750, DOI: 10.1073/pnas.1103407108.Peer-Reviewed Original ResearchCitationsMeSH Keywords and ConceptsThe crystal structure of GXGD membrane protease FlaK
Hu J, Xue Y, Lee S, Ha Y. The crystal structure of GXGD membrane protease FlaK. Nature 2011, 475: 528-531. PMID: 21765428, PMCID: PMC3894692, DOI: 10.1038/nature10218.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsFamily of proteasesFirst crystal structureIntramembrane proteasesPrepilin peptidaseMethanococcus maripaludisMembrane proteasePreflagellin peptidaseFamilial Alzheimer's diseaseVirulence factorsAspartyl proteaseBiochemical analysisProteasePathogenic bacteriaStructural knowledgePresenilinPeptidaseCrystal structureSoluble counterpartActive siteFamilyRational designAspartylBacteriaAlzheimer's diseaseFundamental differences
2007
Open-cap conformation of intramembrane protease GlpG
Wang Y, Ha Y. Open-cap conformation of intramembrane protease GlpG. Proceedings Of The National Academy Of Sciences Of The United States Of America 2007, 104: 2098-2102. PMID: 17277078, PMCID: PMC1892946, DOI: 10.1073/pnas.0611080104.Peer-Reviewed Original ResearchCitationsMeSH Keywords and ConceptsConceptsIntramembrane proteasesEscherichia coli GlpGHydrophilic active sitePutative oxyanion holeActive siteMain-chain amidesPrevious crystallographic analysisRhomboid familyConformational plasticitySer-201Substrate bindingLoop L5GlpGClosed conformationSide portalsOpen conformationHydrophobic side chainsLoop movementOxyanion holeSide chainsPeptide bond hydrolysisLipid bilayersBond hydrolysisProteaseConformation
2006
Crystal structure of a rhomboid family intramembrane protease
Wang Y, Zhang Y, Ha Y. Crystal structure of a rhomboid family intramembrane protease. Nature 2006, 444: 179-180. PMID: 17051161, DOI: 10.1038/nature05255.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsMeSH KeywordsAmino Acid MotifsBinding SitesCatalysisCell MembraneCrystallizationCrystallography, X-RayDNA-Binding ProteinsEndopeptidasesEscherichia coliEscherichia coli ProteinsHydrophobic and Hydrophilic InteractionsMembrane ProteinsModels, MolecularProtein Structure, TertiarySubstrate SpecificityWaterConceptsMembrane proteinsEscherichia coli GlpGÅ resolution crystal structureSite-2 proteaseIntegral membrane proteinsPutative active siteResolution crystal structureHydrophilic active siteRhomboid proteasesIntramembrane proteasesIntramembrane proteolysisTransmembrane segmentsTransmembrane domainActive siteProtease familyMembrane bilayerProtein interiorCore domainGating mechanismGlpGΓ-secretaseHydrophobic environmentCrystal structureProteaseLoop structure
2004
H1 and H7 influenza haemagglutinin structures extend a structural classification of haemagglutinin subtypes
Russell R, Gamblin S, Haire L, Stevens D, Xiao B, Ha Y, Skehel J. H1 and H7 influenza haemagglutinin structures extend a structural classification of haemagglutinin subtypes. Virology 2004, 325: 287-296. PMID: 15246268, DOI: 10.1016/j.virol.2004.04.040.Peer-Reviewed Original ResearchCitationsAltmetricThe X-Ray Structure of an Antiparallel Dimer of the Human Amyloid Precursor Protein E2 Domain
Wang Y, Ha Y. The X-Ray Structure of an Antiparallel Dimer of the Human Amyloid Precursor Protein E2 Domain. Molecular Cell 2004, 15: 343-353. PMID: 15304215, DOI: 10.1016/j.molcel.2004.06.037.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsMembrane protein precursorsX-ray structureSpectrin familyHeparan sulfate proteoglycanDimer interfaceBiological functionsStructure of E2Protein structureProtein precursorPutative ligandE2 domainContinuous helixExtracellular matrixUnexpected resemblanceAntiparallel dimerSulfate proteoglycanAntiparallel orientationPrecursor presentDomainBindsHelixDimerizationSecond monomer
Links & Media
Media
- The co-crystal structure of PIP4K in complex with two 2-amino-dihydropteridinone inhibitors.
- The crystal structure of rhomboid intramembrane protease GlpG.
News
- July 21, 2020Source: Office of Cooperative Research
The Blavatnik Fund for Innovation at Yale Awards $2.6 Million For Faculty Research
- November 18, 2014
The 4th Yale Biophysics & Structural Biology Symposium
- February 24, 2014
Inside the toolbox
- January 15, 2014
Inside the toolbox
Get In Touch
Contacts
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