Interaction of LDL receptor‐related protein 4 (LRP4) with postsynaptic scaffold proteins via its C‐terminal PDZ domain‐binding motif, and its regulation by Ca2+/calmodulin‐dependent protein kinase II

We cloned here a full‐length cDNA of Dem26[ Tian et al. (1999)Mol. Brain Res., 72, 147–157], a member of the low‐density lipoprotein (LDL) receptor gene family from the rat brain. We originally named the corresponding protein synaptic LDL receptor‐related protein (synLRP) [ Tian et al. (2002) Soc. Neurosci. Abstr., 28, 405] and have renamed it LRP4 to accord it systematic nomenclature (GenBankTM accession no. AB073317). LRP4 protein interacted with postsynaptic scaffold proteins such as postsynaptic density (PSD)‐95 via its C‐terminal tail sequence, and associated with N‐methyl‐d‐aspartate (NMDA)‐type glutamate receptor subunit. The mRNA of LRP4 was localized to dendrites, as well as somas, of neuronal cells, and the full‐length protein of 250 kDa was highly concentrated in the brain and localized to various subcellular compartments in the brain, including synaptic fractions. Immunocytochemical study using cultured cortical neurons suggested surface localization in the neuronal cells both in somas and dendrites. Ca2+/calmodulin‐dependent protein kinase II (CaMKII) phosphorylated the C‐terminal cytoplasmic region of LRP4 at Ser1887 and Ser1900, and the phosphorylation at the latter site suppressed the interaction of the protein with PSD‐95 and synapse‐associated protein 97 (SAP97). These findings suggest a postsynaptic role for LRP4, a putative endocytic multiligand receptor, and a mechanism in which CaMKII regulates PDZ‐dependent protein–protein interactions and receptor dynamics.

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