A Tripartite Protein Complex with the Potential to Couple Synaptic Vesicle Exocytosis to Cell Adhesion in Brain

Butz, Stefan; Okamoto, Masaya; Südhof, Thomas C.

doi:10.1016/s0092-8674(00)81736-5

Cited by 523 publications

(588 citation statements)

References 36 publications

(16 reference statements)

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“…3c). This L27 domain-mediated polymerization model is consistent with experimental observations showing that L27 domain-containing scaffold proteins, such as SAP97 and mLin-2, often form large clusters 2,3,11,13,18,19 . During this L27 domainmediated scaffold protein assembly, other protein-binding domains (such as the PDZ and SH3 domains) would be free to recruit their specific target proteins (receptors, ion channels and their downstream partners).…”

Section: Discussionsupporting

confidence: 89%

“…The mammalian orthologs of Lin-2, Lin-7 and Lin-10 are known as mammalian Lin-2 (mLin-2)/CASK, mLin-7/Velis/Mals and mLin-10/X11α/Mint1, respectively 2,6-9 . The mLin-2-mLin-7-mLin-10 tripartite complex has also been observed in the brain 2,6 , and this evolutionarily conserved protein complex has been implicated in the targeting of NMDA receptors and β-catenin assemblies to membrane subdomains in epithelia and neurons 10,11 .A bioinformatics survey reveals that L27 domain-containing proteins are invariably scaffold proteins containing multiple proteinprotein interaction domains without intrinsic enzyme activities 12 . For example, SAP97 and mLin-2/CASK, which are members of a subset of membrane-associated guanylate kinases (MAGUKs), contain one and two L27 domains, respectively, in addition to their PDZ, SH3 and guanylate kinase-like domains.…”

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The tetrameric L27 domain complex as an organization platform for supramolecular assemblies

Feng

Long

Fan

et al. 2004

Nat Struct Mol Biol

100

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Clustering and asymmetric distribution of receptors, ion channels and associated protein complexes are essential to the polarity of neurons and epithelial cells. Such asymmetric targeting of large molecular assemblies is thought to be governed in part by modular scaffold proteins. L27 domain, initially identified in the C. elegans Lin-2 and Lin-7 proteins, is a protein interaction module that exists in a large family of scaffold proteins 1 . Formation of the trimeric Lin-2-Lin-7-Lin-10 complex requires L27 domains 2,3 and has a central role in targeting receptor tyrosine kinase Let-23 signalsome to the basolateral surface of vulval precursor cells 4,5 . Mutations in Lin-2, Lin-7 or Lin-10 lead to a vulvaless phenotype, presumably by mistargeting of 5). The mammalian orthologs of Lin-2, Lin-7 and Lin-10 are known as mammalian Lin-2 (mLin-2)/CASK, mLin-7/Velis/Mals and mLin-10/X11α/Mint1, respectively 2,6-9 . The mLin-2-mLin-7-mLin-10 tripartite complex has also been observed in the brain 2,6 , and this evolutionarily conserved protein complex has been implicated in the targeting of NMDA receptors and β-catenin assemblies to membrane subdomains in epithelia and neurons 10,11 .A bioinformatics survey reveals that L27 domain-containing proteins are invariably scaffold proteins containing multiple proteinprotein interaction domains without intrinsic enzyme activities 12 . For example, SAP97 and mLin-2/CASK, which are members of a subset of membrane-associated guanylate kinases (MAGUKs), contain one and two L27 domains, respectively, in addition to their PDZ, SH3 and guanylate kinase-like domains. The N-terminal L27 domain of SAP97 can form specific heteromeric complexes with the N-terminal L27 domain of mLin-2, Dlg2 and Dlg3, respectively 3,13,14 . The C-terminal L27 domain of mLin-2 specifically binds to the L27 domain of 15). The discovery of L27 domains as specific protein-protein interaction modules capable of forming heteromeric complexes suggests that L27 domains can integrate multiple scaffold proteins into supramolecular assemblies 1,3,13,15,16 . However, the molecular basis of the L27 domain-mediated protein assembly formation remains unclear. The structures of isolated L27 domains and their cognate heteromeric complexes are not known.Here we show that the L27 domain of SAP97 and the N-terminal L27 domain of mLin-2 form a heterotetrameric complex. The structure of the SAP97-mLin-2 L27 complex was solved by NMR spectroscopy. The structure of the complex, together with data derived from various biochemical studies, establishes the roles of specific residues in the formation of the L27 heterotetrameric complex. The structure of the SAP97-mLin-2 L27 complex further suggests a mechanistic model for polymerization of L27 domain scaffold proteins. RESULTS L27 domains form specific heterotetrameric complexesWe first characterized the structural properties of the isolated L27 domains of SAP97 (referred to as L27S below), mLin-7, the N-terminal L27 domain (referred to as L27N below), and the C-terminal L27 domain (ref...

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Section: Discussionsupporting

confidence: 89%

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confidence: 99%

mentioning

confidence: 99%

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The tetrameric L27 domain complex as an organization platform for supramolecular assemblies

Feng

Long

Fan

et al. 2004

Nat Struct Mol Biol

100

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“…Although we cannot detect an interaction of mlin-7 with EGF receptor, ErbB2, or ErbB4 (data not shown), mlin-7 may interact with and localize some receptor at the tight and/or adherens junctions, and may be essential for intact intercellular signal transductions. After the submission of this paper, the sequences of three mammalian lin-7 homologues were reported (Butz et al, 1998). These homologues were shown to make a ternary complex with CASK and X11/Mint in synapses (Duclos et al, 1993;Okamoto and Sudhof, 1997).…”

Section: Discussionmentioning

confidence: 99%

Isolation and characterization of mammalian homologues of Caenorhabditis elegans lin-7: localization at cell-cell junctions

et al. 1999

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“…In Caenorhabditis elegans, mutation of lin-10 (the only X11/Mint homolog in C. elegans) results in mislocalization of the epidermal growth factor receptor, LET-23, and causes a signaling-defective (vulvaless) phenotype 18,20 . The proper localization of LET-23 requires an evolutionary conserved complex of LIN-2, LIN-7 and LIN-10 (CASK, Mals and X11a in mammals) 21 . Mutation of lin-10 also disrupts postsynaptic targeting of glutamate receptor-1 in C. elegans neurons 19 .…”

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Autoinhibition of X11/Mint scaffold proteins revealed by the closed conformation of the PDZ tandem

Long

Feng

Wang

et al. 2005

Nat Struct Mol Biol

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Members of the X11/Mint family of multidomain adaptor proteins are composed of a divergent N terminus, a conserved PTB domain and a pair of C-terminal PDZ domains. Many proteins can interact with the PDZ tandem of X11 proteins, although the mechanism of such interactions is unclear. Here we show that the highly conserved C-terminal tail of X11a folds back and inserts into the target-binding groove of the first PDZ domain. The binding of this tail occludes the binding of other target peptides. This autoinhibited conformation of X11 requires that the two PDZ domains and the entire C-terminal tail be covalently connected to form an integral structural unit. The autoinhibited conformation of the X11 PDZ tandem provides a mechanistic explanation for the unique target-binding properties of the protein and hints at potential regulatory mechanisms for the X11-target interactions.The X11/Mint family of multidomain scaffold proteins comprises three members: X11a/Mint1, X11b/Mint2 and X11g/Mint3 (refs. 1-5). X11a/Mint1 and X11b/Mint2 are neuron-specific proteins, whereas X11g/Mint3 is ubiquitously expressed 2,6-9 . Except for their isoform-specific N-terminal sequences, all X11/Mint proteins contain a central PTB domain and two C-terminal PDZ domains arranged in tandem (Fig. 1a). The PTB domain binds to the C-terminal YENPTY motif of amyloid precursor protein (APP). This interaction prolongs the half-life of cellular APP, thereby slowing the production of amyloid-b peptide 3,10-13 . A growing number of proteins that bind to the PDZ domains of X11/Mint proteins have been identified, including presenilin 13,14 , calcium channels 15 , neurexin 5 and AMPA receptors 16 . Although not directly involved in binding APP, the PDZ tandem of X11/Mint proteins has an indispensable role in PTB domain-mediated APP stabilization 13,17 . Available experimental data indicate that the binding of target proteins to isolated PDZ domains is distinctly different from the binding of those targets to two PDZ domains connected in tandem 13,14 . Current understanding of the structural and biochemical properties of the X11 PDZ domains cannot explain their unique target-binding properties.X11/Mint proteins are also implicated in polarized trafficking of receptors and ion channels to plasma membranes [18][19][20] . In Caenorhabditis elegans, mutation of lin-10 (the only X11/Mint homolog in C. elegans) results in mislocalization of the epidermal growth factor receptor, LET-23, and causes a signaling-defective (vulvaless) phenotype 18,20 . The proper localization of LET-23 requires an evolutionary conserved complex of LIN-2, LIN-7 and LIN-10 (CASK, Mals and X11a in mammals) 21 . Mutation of lin-10 also disrupts postsynaptic targeting of glutamate receptor-1 in C. elegans neurons 19 . X11a/Mint1 has been implicated in the kinesin-mediated transport of NMDA receptors to synapses 22,23 and is preferentially expressed in inhibitory neurons 24 . Deletion of X11a/Mint1 in mice impairs GABAergic synaptic transmission 24 . That X11a/Mint1 knockout study, however...

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A Tripartite Protein Complex with the Potential to Couple Synaptic Vesicle Exocytosis to Cell Adhesion in Brain

Cited by 523 publications

References 36 publications

The tetrameric L27 domain complex as an organization platform for supramolecular assemblies

The tetrameric L27 domain complex as an organization platform for supramolecular assemblies

Isolation and characterization of mammalian homologues of Caenorhabditis elegans lin-7: localization at cell-cell junctions

Autoinhibition of X11/Mint scaffold proteins revealed by the closed conformation of the PDZ tandem

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