title: DHHC5 interacts with PDZ domain 3 of post-synaptic density-95 (PSD-95) protein and plays a role in learning and memory.
abstract: A family of integral membrane proteins containing a signature DHHC motif has been shown to display protein S-acyltransferase activity, modifying cysteine residues in proteins with fatty acids. The physiological roles of these proteins have largely been unexplored. Here we report that mice homozygous for a hypomorphic allele of a previously uncharacterized member, DHHC5, are born at half the expected rate, and survivors show a marked deficit in contextual fear conditioning, an indicator of defective hippocampal-dependent learning. DHHC5 is highly enriched in a post-synaptic density preparation and co-immunoprecipitates with post-synaptic density protein-95 (PSD-95), an interaction that is mediated through binding of the carboxyl terminus of DHHC5 and the PDZ3 domain of PSD-95. Immunohistochemistry demonstrated that DHHC5 is expressed in the CA3 and dentate gyrus in the hippocampus. These findings point to a previously unsuspected role for DHHC5 in post-synaptic function affecting learning and memory.
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8593, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.forename: Jie
authors.initials: J
authors.lastname: Hu
authors.forename: Klemens
authors.initials: K
authors.lastname: Höfer
authors.forename: Andrew M S
authors.initials: AM
authors.lastname: Wong
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Cooper
authors.forename: Shari G
authors.initials: SG
authors.lastname: Birnbaum
authors.forename: Robert E
authors.initials: RE
authors.lastname: Hammer
authors.forename: Sandra L
authors.initials: SL
authors.lastname: Hofmann
mesh_terms: D000217:Acyltransferases / Q000096:biosynthesis* / Q000235:genetics; D000483:Alleles; D000818:Animals; D002460:Cell Line; D018891:Dentate Gyrus / Q000378:metabolism*; D000076122:Disks Large Homolog 4 Protein; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D051528:Guanylate Kinases; D006720:Homozygote; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D007858:Learning / Q000502:physiology; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism*; D008568:Memory / Q000502:physiology*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D054731:PDZ Domains; D051381:Rats
chemical_list: D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; C501449:Dlg4 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D000217:Acyltransferases; C549503:DHHC5 protein, mouse; D051528:Guanylate Kinases