HOMER1 explained

Homer protein homolog 1 or Homer1 is a neuronal protein that in humans is encoded by the HOMER1 gene.^{[1] [2] [3]} Other names are Vesl and PSD-Zip45.

Structure

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.^{[4] [5]} 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.^[5] 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 central nervous system as well as peripheral tissue including heart, kidney, ovary, testis, and skeletal muscle. Subcellularly in neurons, Homer1 is concentrated in postsynaptic structures and constitutes a major part of the 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), Shank, transient receptor potential canonical (TRPC) family channels, drebrin, oligophrenin, dynamin3, CENTG1, and ryanodin receptor.^{[1] [3] [6] [7] [8] [9]} 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.^[6] Also, through crosslinking another multimeric protein Shank, it is proposed to comprise a core of the postsynaptic density.^[5]

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.^[10] 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.^[11]

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.

Rapid antidepressant effects

Homer1a switches mGluR5 signaling to increase AMPA receptor activity for the rapid antidepressant actions of sleep deprivation.^[12]

See also

• HOMER2
• HOMER3

Further reading

• Xiao B, Tu JC, Worley PF . Homer: a link between neural activity and glutamate receptor function . Current Opinion in Neurobiology . 10 . 3 . 370–374 . June 2000 . 10851183 . 10.1016/S0959-4388(00)00087-8 . 8699597 .
• Maruyama K, Sugano S . Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides . Gene . 138 . 1–2 . 171–174 . January 1994 . 8125298 . 10.1016/0378-1119(94)90802-8 .
• Hillier LD, Lennon G, Becker M, Bonaldo MF, Chiapelli B, Chissoe S, Dietrich N, DuBuque T, Favello A, Gish W, Hawkins M, Hultman M, Kucaba T, Lacy M, Le M, Le N, Mardis E, Moore B, Morris M, Parsons J, Prange C, Rifkin L, Rohlfing T, Schellenberg K, Bento Soares M, Tan F, Thierry-Meg J, Trevaskis E, Underwood K, Wohldman P, Waterston R, Wilson R, Marra M . 6 . Generation and analysis of 280,000 human expressed sequence tags . Genome Research . 6 . 9 . 807–828 . September 1996 . 8889549 . 10.1101/gr.6.9.807 . free .
• Brakeman PR, Lanahan AA, O'Brien R, Roche K, Barnes CA, Huganir RL, Worley PF . Homer: a protein that selectively binds metabotropic glutamate receptors . Nature . 386 . 6622 . 284–288 . March 1997 . 9069287 . 10.1038/386284a0 . 1997Natur.386..284B . 4346579 .
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S . Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library . Gene . 200 . 1–2 . 149–156 . October 1997 . 9373149 . 10.1016/S0378-1119(97)00411-3 .
• Tu JC, Xiao B, Naisbitt S, Yuan JP, Petralia RS, Brakeman P, Doan A, Aakalu VK, Lanahan AA, Sheng M, Worley PF . 6 . Coupling of mGluR/Homer and PSD-95 complexes by the Shank family of postsynaptic density proteins . Neuron . 23 . 3 . 583–592 . July 1999 . 10433269 . 10.1016/S0896-6273(00)80810-7 . 16429070 . free .
• Roche KW, Tu JC, Petralia RS, Xiao B, Wenthold RJ, Worley PF . Homer 1b regulates the trafficking of group I metabotropic glutamate receptors . The Journal of Biological Chemistry . 274 . 36 . 25953–25957 . September 1999 . 10464340 . 10.1074/jbc.274.36.25953 . free .
• Minakami R, Kato A, Sugiyama H . Interaction of Vesl-1L/Homer 1c with syntaxin 13 . Biochemical and Biophysical Research Communications . 272 . 2 . 466–471 . June 2000 . 10833436 . 10.1006/bbrc.2000.2777 .
• Ango F, Prézeau L, Muller T, Tu JC, Xiao B, Worley PF, Pin JP, Bockaert J, Fagni L . 6 . Agonist-independent activation of metabotropic glutamate receptors by the intracellular protein Homer . Nature . 411 . 6840 . 962–965 . June 2001 . 11418862 . 10.1038/35082096 . 4417727 .
• Wistow G, Bernstein SL, Wyatt MK, Fariss RN, Behal A, Touchman JW, Bouffard G, Smith D, Peterson K . 6 . 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 . June 2002 . 12107410 .
• Feng W, Tu J, Yang T, Vernon PS, Allen PD, Worley PF, Pessah IN . Homer regulates gain of ryanodine receptor type 1 channel complex . The Journal of Biological Chemistry . 277 . 47 . 44722–44730 . November 2002 . 12223488 . 10.1074/jbc.M207675200 . free .
• Hwang SY, Wei J, Westhoff JH, Duncan RS, Ozawa F, Volpe P, Inokuchi K, Koulen P . 6 . 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 . August 2003 . 12810060 . 10.1016/S0143-4160(03)00082-4 .
• Norton N, Williams HJ, Williams NM, Spurlock G, Zammit S, Jones G, Jones S, Owen R, O'Donovan MC, Owen MJ . 6 . 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 . July 2003 . 12815733 . 10.1002/ajmg.b.20032 . 25053099 .
• Westhoff JH, Hwang SY, Duncan RS, Ozawa F, Volpe P, Inokuchi K, Koulen P . Vesl/Homer proteins regulate ryanodine receptor type 2 function and intracellular calcium signaling . Cell Calcium . 34 . 3 . 261–269 . September 2003 . 12887973 . 10.1016/S0143-4160(03)00112-X .
• Yuan JP, Kiselyov K, Shin DM, Chen J, Shcheynikov N, Kang SH, Dehoff MH, Schwarz MK, Seeburg PH, Muallem S, Worley PF . 6 . Homer binds TRPC family channels and is required for gating of TRPC1 by IP3 receptors . Cell . 114 . 6 . 777–789 . September 2003 . 14505576 . 10.1016/S0092-8674(03)00716-5 . 10552676 . free .
• Rong R, Ahn JY, Huang H, Nagata E, Kalman D, Kapp JA, Tu J, Worley PF, Snyder SH, Ye K . 6 . PI3 kinase enhancer-Homer complex couples mGluRI to PI3 kinase, preventing neuronal apoptosis . Nature Neuroscience . 6 . 11 . 1153–1161 . November 2003 . 14528310 . 10.1038/nn1134 . 807407 .

Notes and References

1. Shiraishi-Yamaguchi Y, Furuichi T . The Homer family proteins . Genome Biology . 8 . 2 . 206 . 2007 . 17316461 . 1852408 . 10.1186/gb-2007-8-2-206 . free .
2. Tu JC, Xiao B, Yuan JP, Lanahan AA, Leoffert K, Li M, Linden DJ, Worley PF . 6 . Homer binds a novel proline-rich motif and links group 1 metabotropic glutamate receptors with IP3 receptors . Neuron . 21 . 4 . 717–726 . October 1998 . 9808459 . 10.1016/S0896-6273(00)80589-9 . 2851554 . free .
3. Web site: Entrez Gene: HOMER1 homer homolog 1 (Drosophila).
4. Hayashi MK, Ames HM, Hayashi Y . Tetrameric hub structure of postsynaptic scaffolding protein homer . The Journal of Neuroscience . 26 . 33 . 8492–8501 . August 2006 . 16914674 . 6674353 . 10.1523/JNEUROSCI.2731-06.2006 . free .
5. Hayashi MK, Tang C, Verpelli C, Narayanan R, Stearns MH, Xu RM, Li H, Sala C, Hayashi Y . 6 . The postsynaptic density proteins Homer and Shank form a polymeric network structure . Cell . 137 . 1 . 159–171 . April 2009 . 19345194 . 2680917 . 10.1016/j.cell.2009.01.050 .
6. Xiao B, Tu JC, Petralia RS, Yuan JP, Doan A, Breder CD, Ruggiero A, Lanahan AA, Wenthold RJ, Worley PF . 6 . Homer regulates the association of group 1 metabotropic glutamate receptors with multivalent complexes of homer-related, synaptic proteins . Neuron . 21 . 4 . 707–716 . October 1998 . 9808458 . 10.1016/S0896-6273(00)80588-7 . 16431031 . free .
7. Rong R, Ahn JY, Huang H, Nagata E, Kalman D, Kapp JA, Tu J, Worley PF, Snyder SH, Ye K . 6 . PI3 kinase enhancer-Homer complex couples mGluRI to PI3 kinase, preventing neuronal apoptosis . Nature Neuroscience . 6 . 11 . 1153–1161 . November 2003 . 14528310 . 10.1038/nn1134 . 807407 .
8. Hwang SY, Wei J, Westhoff JH, Duncan RS, Ozawa F, Volpe P, Inokuchi K, Koulen P . 6 . 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 . August 2003 . 12810060 . 10.1016/S0143-4160(03)00082-4 .
9. Feng W, Tu J, Yang T, Vernon PS, Allen PD, Worley PF, Pessah IN . Homer regulates gain of ryanodine receptor type 1 channel complex . The Journal of Biological Chemistry . 277 . 47 . 44722–44730 . November 2002 . 12223488 . 10.1074/jbc.M207675200 . free .
10. Sala C, Futai K, Yamamoto K, Worley PF, Hayashi Y, Sheng M . Inhibition of dendritic spine morphogenesis and synaptic transmission by activity-inducible protein Homer1a . The Journal of Neuroscience . 23 . 15 . 6327–6337 . July 2003 . 12867517 . 6740555 . 10.1523/JNEUROSCI.23-15-06327.2003 .
11. Meyer D, Bonhoeffer T, Scheuss V . Balance and stability of synaptic structures during synaptic plasticity . Neuron . 82 . 2 . 430–443 . April 2014 . 24742464 . 10.1016/j.neuron.2014.02.031 . free .
12. Albert PR . Targeting Homer1a for Rapid Antidepressant Effects . Neuron . 104 . 2 . 182–183 . October 2019 . 31647890 . 10.1016/j.neuron.2019.10.003 . 204837754 . free .