Structure of the Homer EVH1 Domain-Peptide Complex Reveals a New Twist in Polyproline Recognition

Beneken, J.; Tu, Jian Cheng; Xiao, Bo; Nuriya, Mutsuo; Yuan, Joseph P.; Worley, Paul F.; Leahy, Daniel J.

doi:10.1016/s0896-6273(00)81145-9

Cited by 161 publications

(185 citation statements)

References 71 publications

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“…With the exception of the recently characterized Homer1g [111], exons 2-5 encode an Enabled/ vasodilator-stimulated phosphoprotein (Vasp) homology 1 (EVH1) domain [119,120], which is similar in sequence to other Ena/Vasp proteins that regulate cytoskeleton dynamics [121].…”

Section: Molecular Aspects Of Homer Proteinsmentioning

confidence: 99%

Homers regulate drug-induced neuroplasticity: Implications for addiction

Szumlinski

Ary

Lominac

2008

Biochemical Pharmacology

118

160

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Drug addiction is a chronic, relapsing disorder, characterized by an uncontrollable motivation to seek and use drugs. Converging clinical and preclinical observations implicate pathologies within the corticolimbic glutamate system in the genetic predisposition to, and the development of, an addicted phenotype. Such observations pose cellular factors regulating glutamate transmission as likely molecular candidates in the etiology of addiction. Members of the Homer family of proteins regulate signal transduction through, and the trafficking of, glutamate receptors, as well as maintain and regulate extracellular glutamate levels in corticolimbic brain regions. This review summarizes the existing data implicating the Homer family of protein in acute behavioral and neurochemical sensitivity to drugs of abuse, the development of drug-induced neuroplasticity, as well as other behavioral and cognitive pathologies associated with an addicted state.

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Section: Molecular Aspects Of Homer Proteinsmentioning

confidence: 99%

Homers regulate drug-induced neuroplasticity: Implications for addiction

Szumlinski

Ary

Lominac

2008

Biochemical Pharmacology

118

160

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“…Mutation and structural analysis revealed that the EVH1 domain binds the sequence PPXXF [12][13][14]. Subsequent work indicated that the EVH1 domain can also bind the sequence øPPXF and the novel ligand LPSSP [15].…”

Section: Homers Localization and Binding To Ca 2+ Signaling Proteinsmentioning

confidence: 99%

“…The effect of Homer1 in neuronal mGluRs Ca 2+ signaling appears to be neuron-type specific. Homer1 binds to the proline-rich motifs PPXXF in the C terminus of mGluRs [12] and the N-terminus of the IP 3 Rs [15], linking them to the Shank family proteins in the PSD to form a Ca 2+ signaling complex [9,29]. Homer1 and Shank target the mGluRs to the plasma membrane when co-expressed in HeLa and other cell types [6,8,9,11,16,17,26].…”

Section: Homer1 In Neuronal Ca 2+ Signalingmentioning

confidence: 99%

Homer proteins in Ca2+ signaling by excitable and non-excitable cells

et al. 2007

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Homers are scaffolding proteins that bind Ca 2+ signaling proteins in cellular microdomains. The Homers participate in targeting and localization of Ca 2+ signaling proteins in signaling complexes. However, recent work showed that the Homers are not passive scaffolding proteins, but rather they regulate the activity of several proteins within the Ca 2+ signaling complex in an isoform specific manner. Homer2 increases the GAP activity of RGS proteins and PLCβ that accelerate the GTPase activity of Gα subunits. Homer1 gates the activity of TRPC channels, controls the rates of their translocation and retrieval from the plasma membrane and mediates the conformational coupling between TRPC channels and IP 3 Rs. Homer1 stimulates the activity of the cardiac and neuronal Ltype Ca 2+ channels Ca v 1.2 and Ca v 1.3. Homer1 also mediates the communication between the cardiac and smooth muscle ryanodine receptor RyR2 and Ca v 1.2 to regulate E-C coupling. In many cases the Homers function as a buffer to reduce the intensity of Ca 2+ signaling and create a negative bias that can be reversed by the immediate early gene form of Homer 1. Hence, the Homers should be viewed as the buffers of Ca 2+ signaling that ensure a high spatial and temporal fidelity of the Ca 2+ signaling and activation of downstream effects.

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“…These genes encode 47-48 kDa proteins that feature an N-terminal Enabled/Vasp homology (EVH1) (Gertler et al, 1996;Beneken et al, 2000) domain of the Ena/VASP protein family (Ponting and Phillips, 1997) and a C-terminal coiled-coil domain and leucine zipper (Kato et al, 1998;Sun et al, 1998;Xiao et al, 1998;Tadokoro et al, 1999) for oligomerization. The EVH1 domain binds a proline-rich motif (PPXXFR) Beneken et al, 2000) in key components of synaptic signal transduction pathways for calciuminduced and transmitter-induced calcium release (C/TICR). This motif resides in the metabotropic glutamate receptors mGluR1a and mGluR5a/b, in ryanodine receptors (RyRs), in inositol triphosphate [Ins(1,4,5)P3] receptors , and in Shank proteins that are part of the NMDA receptor-associated PSD-95 complex .…”

Section: Abstract: Immediate Early Gene; Induced Neuronal Activity; mentioning

confidence: 99%

“…Exon 1 harbors the 5Ј-untranslated region and contains the translational initiation codon ATG at its 3Ј end. The EVH1 domain, characteristic of all Homor proteins (Beneken et al, 2000), is encoded by exons 2-5, whereas the coiled-coil and leucine zipper domains of the long Homor 1 forms are encoded by exons 6 -10. Exon 10 features 186 nucleotides of translated sequence followed by ϳ2.7 kb of 3Ј UTR.…”

Section: Homer 1 Gene Organizationmentioning

confidence: 99%

Synaptic Activity-Induced Conversion of Intronic to Exonic Sequence in Homer 1 Immediate Early Gene Expression

et al. 2002

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Three Homer genes regulate the activity of metabotropic glutamate receptors mGluR1a and mGluR5 and their coupling to releasable intracellular Ca2+pools and ion channels. Only the Homer 1 gene evolved bimodal expression of constitutive (Homer 1b and c) and immediate early gene (IEG) products (Homer 1a and Ania 3). The IEG forms compete functionally with the constitutive Homer proteins. The complex expression of the Homer 1 gene, unique for IEGs, focused our attention on the gene organization. In contrast to most IEGs, which have genes that are <5 kb, the Homer 1 gene was found to span ∼100 kb. The constitutive Homer 1b/c forms are encoded by exons 1–10, whereas the IEG forms are encoded by exons 1–5 and parts of intron 5. RNase protection demonstrated a >10-fold activity-dependent increase in mRNA levels exclusively for the IEG forms. Moreover, fluorescentin situhybridization documented that new primary Homer 1 transcripts are induced in neuronal nuclei within a few minutes after seizure, typical of IEGs, and that Homer 1b-specific exons are excluded from the activity-induced transcripts. Thus, at the resting state of the neurons, the entire gene is constitutively transcribed at low levels to yield Homer 1b/c transcripts. Neuronal activity sharply increases the rate of transcription initiation, with most transcripts now ending within the central intron. These coordinate transcriptional events rapidly convert a constitutive gene to an IEG and regulate the expression of functionally different Homer 1 proteins.

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Structure of the Homer EVH1 Domain-Peptide Complex Reveals a New Twist in Polyproline Recognition

Cited by 161 publications

References 71 publications

Homers regulate drug-induced neuroplasticity: Implications for addiction

Homers regulate drug-induced neuroplasticity: Implications for addiction

Homer proteins in Ca2+ signaling by excitable and non-excitable cells

Synaptic Activity-Induced Conversion of Intronic to Exonic Sequence in Homer 1 Immediate Early Gene Expression

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