Homer1 protein has an N-terminal EVH1 domain, involved in protein interaction, and a C-terminal coiled-coil domain involved in self association. It consists of two major 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.[8][9] 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 (~50nm) coiled-coil domain.[9] Mammals have Homer2 and Homer3, in addition to Homer1, which have similar domain structure. They also have similar alternatively spliced forms.
Dimeric-tetrameric coiled-coil domain of Homer1b. PDB rendering based on 3CVE.
Notably, the expression of Homer1a is induced by neuronal activity while that of Homer1b and 1c are constitutive. Thus Homer1a is classified as an immediate early gene. Homer1a, acts as a natural 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 dendritic spine structure.[6][14] Therefore, the short form of Homer is considered to be a part of a mechanism of homeostatic plasticity that dampens the neuronal responsiveness when input activity is too high. The long form Homer1c plays a role in synaptic plasticity and the stabilization of synaptic changes during long-term potentiation.[15]
The coiled-coil domain is reported to interact with syntaxin13 and activated Cdc42. The interaction with Cdc42 inhibit the activity of Cdc42 to remodel dendritic spine structure.
Homer1a switches mGluR5 signaling to increase AMPA receptor activity for the rapid antidepressant actions of sleep deprivation.[16]
Hwang SY, Wei J, Westhoff JH, Duncan RS, Ozawa F, Volpe P, etal. (August 2003). "Differential functional interaction of two Vesl/Homer protein isoforms with ryanodine receptor type 1: a novel mechanism for control of intracellular calcium signaling". Cell Calcium. 34 (2): 177–184. doi:10.1016/S0143-4160(03)00082-4. PMID12810060.
Maruyama K, Sugano S (January 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–174. doi:10.1016/0378-1119(94)90802-8. PMID8125298.
Brakeman PR, Lanahan AA, O'Brien R, Roche K, Barnes CA, Huganir RL, Worley PF (March 1997). "Homer: a protein that selectively binds metabotropic glutamate receptors". Nature. 386 (6622): 284–288. Bibcode:1997Natur.386..284B. doi:10.1038/386284a0. PMID9069287. S2CID4346579.
Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (October 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–156. doi:10.1016/S0378-1119(97)00411-3. PMID9373149.
Minakami R, Kato A, Sugiyama H (June 2000). "Interaction of Vesl-1L/Homer 1c with syntaxin 13". Biochemical and Biophysical Research Communications. 272 (2): 466–471. doi:10.1006/bbrc.2000.2777. PMID10833436.
Ango F, Prézeau L, Muller T, Tu JC, Xiao B, Worley PF, etal. (June 2001). "Agonist-independent activation of metabotropic glutamate receptors by the intracellular protein Homer". Nature. 411 (6840): 962–965. doi:10.1038/35082096. PMID11418862. S2CID4417727.
Wistow G, Bernstein SL, Wyatt MK, Fariss RN, Behal A, Touchman JW, etal. (June 2002). "Expressed sequence tag analysis of human RPE/choroid for the NEIBank Project: over 6000 non-redundant transcripts, novel genes and splice variants". Molecular Vision. 8: 205–220. PMID12107410.
Hwang SY, Wei J, Westhoff JH, Duncan RS, Ozawa F, Volpe P, etal. (August 2003). "Differential functional interaction of two Vesl/Homer protein isoforms with ryanodine receptor type 1: a novel mechanism for control of intracellular calcium signaling". Cell Calcium. 34 (2): 177–184. doi:10.1016/S0143-4160(03)00082-4. PMID12810060.
Norton N, Williams HJ, Williams NM, Spurlock G, Zammit S, Jones G, etal. (July 2003). "Mutation screening of the Homer gene family and association analysis in schizophrenia". American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics. 120B (1): 18–21. doi:10.1002/ajmg.b.20032. PMID12815733. S2CID25053099.
Westhoff JH, Hwang SY, Duncan RS, Ozawa F, Volpe P, Inokuchi K, Koulen P (September 2003). "Vesl/Homer proteins regulate ryanodine receptor type 2 function and intracellular calcium signaling". Cell Calcium. 34 (3): 261–269. doi:10.1016/S0143-4160(03)00112-X. PMID12887973.