HOMER1

Homer protein homolog 1 or Homer1 is a neuronal is_associated_with::protein that in humans is encoded by the HOMER1 is_associated_with::gene. Other names are Vesl and PSD-Zip45.

Structure
Homer1 is_associated_with::protein has an N-terminal is_associated_with::EVH1 domain, involved in protein interaction, and a C-terminal is_associated_with::coiled-coil domain involved in self association. It consists of two major is_associated_with::splice variants, short-form (Homer1a) and long-form (Homer1b and c). Homer1a has only EVH1 domain and is monomeric while Homer1b and 1c have both EVH1 and coiled-coil domains and are tetrameric. The coiled-coil can be further separated into N-terminal half and C-terminal half. The N-terminal half of the coiled-coil domain is predicted to be a parallel dimer while the C-terminus half is a hybrid of dimeric and anti-parallel tetrameric coiled-coil. As a whole, long Homer is predicted to have a dumbbell-like structure where two pairs of EVH1 domains are located on two sides of long (~50 nm) coiled-coil domain. Mammals have Homer2 and Homer3, in addition to Homer1, which have similar domain structure. They also have similar alternatively spliced forms.



Tissue distribution
Homer1 is expressed widely in the is_associated_with::central nervous system as well as peripheral tissue including is_associated_with::heart, is_associated_with::kidney, is_associated_with::ovary, is_associated_with::testis, and is_associated_with::skeletal muscle. Subcellularly in neurons, Homer1 is concentrated in postsynaptic structures and constitutes a major part of the is_associated_with::postsynaptic density.

Function
EVH1 domain interacts with PPXXF motif. This sequence motif exists in group 1 metabotrophic glutamate receptor (mGluR1 and mGluR5), IP3 receptors (IP3R), is_associated_with::Shank, transient receptor potential canonical (TRPC) family channels, is_associated_with::drebrin, is_associated_with::oligophrenin, dynamin3, is_associated_with::CENTG1, and ryanodin receptor. Through its tetrameric structure, long forms of Homer (such as Homer1b and Homer1c) are proposed to cross link different proteins. For example, group 1 mGluR is crossed linked with its signaling downstream, IP3 receptor. Also, through crosslinking another multimeric protein Shank, it is proposed to comprise a core of the is_associated_with::postsynaptic density.

Notably, the expression of Homer1a is induced by neuronal activity while that of Homer1b and 1c are constitutive. Thus Homer1a is classified as an is_associated_with::immediate early gene. Homer1a, acts as a natural is_associated_with::dominant negative form that blocks interaction between long-forms and their ligand proteins by competing with the EVH1 binding site on the ligand proteins. In this way, the short form of Homer uncouples mGluR signaling and also shrinks is_associated_with::dendritic spine structure. Therefore, the short form of Homer is considered to be a part of a mechanism of is_associated_with::homeostatic plasticity that dampens the neuronal responsiveness when input activity is too high. The long form Homer1c plays a role in is_associated_with::synaptic plasticity and the stabilization of synaptic changes during is_associated_with::long-term potentiation.

The coiled-coil domain is reported to interact with is_associated_with::syntaxin13 and activated is_associated_with::Cdc42. The interaction with Cdc42 inhibit the activity of Cdc42 to remodel dendritic spine structure.