DHHC5 interacts with PDZ domain 3 of post-synaptic density-95 (PSD-95) protein and plays a role in learning and memory.
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.
Li
Yi
Y
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8593, USA.
Hu
Jie
J
Höfer
Klemens
K
Wong
Andrew M S
AM
Cooper
Jonathan D
JD
Birnbaum
Shari G
SG
Hammer
Robert E
RE
Hofmann
Sandra L
SL
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
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