Coordinated Folding and Association of the LIN-2, -7 (L27) Domain

Harris, Baruch Z.; Venkatasubrahmanyam, Shivkumar; Lim, Wendell A.

doi:10.1074/jbc.m205856200

Cited by 23 publications

(16 citation statements)

References 42 publications

(59 reference statements)

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“…Similarly, we would speculate that this L27 region is not required in Stardust because of the larger amino terminus that can fill this role. Previous circular dichroism study suggested that L27 domains are largely unfolded individually, but when associated with their heterodimerization partners they show a significant increase in helicity as well as a cooperative unfolding transition with increasing temperature (29). We propose that PALS1 may have two conformational states in its amino terminus.…”

Section: Discussionmentioning

confidence: 90%

Tight Junction Protein Par6 Interacts with an Evolutionarily Conserved Region in the Amino Terminus of PALS1/Stardust

Wang¹,

Hurd

Margolis

2004

Journal of Biological Chemistry

113

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Tight junctions are the structures in mammalian epithelial cells that separate the apical and basolateral membranes and may also be important in the establishment of cell polarity. Two evolutionarily conserved multiprotein complexes, Crumbs-PALS1 (Stardust)-PATJ and Cdc42-Par6-Par3-atypical protein kinase C, have been implicated in the assembly of tight junctions and in polarization of Drosophila melanogaster epithelia. These two complexes have been linked physically and functionally by an interaction between PALS1 and Par6. Here we identify an evolutionarily conserved region in the amino terminus of PALS1 as the Par6 binding site and identify valine and aspartic acid residues in this region as essential for interacting with the PDZ domain of Par6. We have also characterized, in more detail, the amino terminus of Drosophila Stardust and demonstrate that the interaction mechanism between Stardust and Drosophila Par6 is evolutionarily conserved. Par6 interferes with PATJ in binding PALS1, and these two interactions do not appear to function synergistically. Taken together, these results define the molecular mechanisms linking two conserved polarity complexes.Epithelial cells possess asymmetry with respect to the apicobasal axis reflected by the differential distribution of proteins and lipids in the apical and basolateral surfaces (1). Polarized mammalian epithelial cells have a tight junctional seal, which serves as a physical barrier that separates apical and basolateral membranes. It has been shown that proteins containing the PDZ (postsynaptic density-95/discs large/ZO-1) domain play an important role during cell polarization (2), and multiple PDZ protein complexes are involved in the assembly and maintenance of tight junctions.One of the major groups of PDZ proteins is the membraneassociated guanylate kinase protein, which has one or more PDZ domains as well as an Src homology 3 domain and a noncatalytic guanylate kinase domain. Genetic and biochemical studies in Drosophila melanogaster have shown that membrane-associated guanylate kinase protein Stardust (Sdt) interacts with the transmembrane protein Crumbs (Crb) through its PDZ domain, and mutations in either Crb or Sdt cause polarity defects in Drosophila epithelia (3). The mammalian homologue of Sdt is PALS1 (protein associated with Lin seven) (4). Like Sdt, the PDZ domain of PALS1 binds the C-terminal tail of mammalian Crb isoforms, and PALS1 also interacts with a multi-PDZ domain protein, PATJ (PALS1-associated tight junction protein), through L27 (Lin-2 and Lin-7) domain dimerization (4, 5). The Crb-PALS1-PATJ complex localizes to the tight junctions of mammalian epithelial cells, and the disruption of the complex leads to defects in cell polarity (6). Similarly, the Drosophila PATJ homologue, formerly known as discs lost (Dlt) (7,8), can interact with the L27 domain of Sdt. Therefore, the analogous complex in D. melanogaster is Crb-Sdt-PATJ.Another evolutionarily conserved tight junction complex is composed of PDZ proteins Par3, Par6, and aPKC and the...

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Section: Discussionmentioning

confidence: 90%

Tight Junction Protein Par6 Interacts with an Evolutionarily Conserved Region in the Amino Terminus of PALS1/Stardust

Wang¹,

Hurd

Margolis

2004

Journal of Biological Chemistry

113

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“…The DLG3:SAP97 interaction may be different in that it requires one helix from each L27 domain of DLG3 to form a stable complex with SAP97. However, in circular dichroism studies of the L27 domains of mLIN-7, mLIN-2, and orthologues, Harris et al found that L27 domains seem to be largely unfolded until binding to another L27 domain (26). Thus, more structural studies of L27 domains will be required before any definitive conclusions can be reached.…”

Section: Discussionmentioning

confidence: 99%

Identification of Multiple Binding Partners for the Amino-terminal Domain of Synapse-associated Protein 97

Karnak¹,

Lee²,

Margolis

2002

Journal of Biological Chemistry

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“…However, in all cases, all assemblies are built from the fundamental unit of a heterodimer. This core dimer unit displays an exclusive preference for heterodimerization versus homodimerization: typically, when only one L27 domain molecule is present, there is no evidence for folding into a homomer structure (11). The obligate heteromeric assembly of L27 domains is thought to be fundamental to its basic function of directing the formation of specific heteromeric supramolecular assemblies.…”

mentioning

confidence: 99%

“…L27 domains, which are ϳ60 residues (28), are largely unfolded in isolation, but fold to form a helical heterodimer upon interaction with the proper heterotypic partner (11). In some cases, two heterodimers can further oligomerize to form a higher order tetramer (29 -31).…”

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confidence: 99%

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A General Model for Preferential Hetero-oligomerization of LIN-2/7 Domains

Petrosky

Löhr

et al. 2005

Journal of Biological Chemistry

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LIN-2/7 (L27) domains are protein interaction modules that preferentially hetero-oligomerize, a property critical for their function in directing specific assembly of supramolecular signaling complexes at synapses and other polarized cell-cell junctions. We have solved the solution structure of the heterodimer composed of the L27 domains from LIN-2 and LIN-7. Comparison of this structure with other L27 domain structures has allowed us to formulate a general model for why most L27 domains form an obligate heterodimer complex. L27 domains can be divided in two types (A and B), with each heterodimer comprising an A/B pair. We have identified two keystone positions that play a central role in discrimination. The residues at these positions are energetically acceptable in the context of an A/B heterodimer, but would lead to packing defects or electrostatic repulsion in the context of A/A and B/B homodimers. As predicted by the model, mutations of keystone residues stabilize normally strongly disfavored homodimers. Thus, L27 domains are specifically optimized to avoid homodimeric interactions.Accurate transmission of cell signaling information often requires the proper co-assembly of partner proteins (1). In eukaryotes, many of these assembly interactions are mediated by modular protein-protein interaction domains. Because these modular domains often compose large families of domains, discrimination between related domains is critical; lack of specificity leads to promiscuous interactions and improper signaling (2). Thus, it is important to understand the molecular basis by which protein interaction domains recognize their correct partner but simultaneously discriminate against closely related but incorrect partners.Modular interaction domains play a central role in organizing polarized sites of cell-cell communication. At such sites of polarization, signaling proteins are organized into specific assemblies by scaffold proteins. The postsynaptic density in neurons (3, 4), tight junction in epithelial cells (5), and immune synapse (6) are examples of highly organized signaling assembly coordinated by such scaffold proteins. In neurons and epithelial cells, PDZ (PSD95/DLG-1/ZO-1) domain-containing scaffold molecules play a central role in directing the trafficking and assembly of receptors and downstream effectors (7).More recently, many of these PDZ domain-containing scaffold proteins have been found to interact with one another to form higher order supramolecular complexes (8, 9). These higher order interactions are mediated primarily by a novel type of protein interaction domain referred to as the LIN-2/7 (L27) 2 domain (10 -14) (Fig. 1A). L27 domains have been found only within metazoan scaffold proteins (15), and several examples are shown in Fig. 1B. To date, there are 34 known human proteins containing L27 domains (15). Several of these scaffold proteins form specific heterotrimer complexes (16 -19), the assembly of which is mediated directly by L27 domains. For example, in Caenorhabditis elegans, the epidermal g...

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Coordinated Folding and Association of the LIN-2, -7 (L27) Domain

Cited by 23 publications

References 42 publications

Tight Junction Protein Par6 Interacts with an Evolutionarily Conserved Region in the Amino Terminus of PALS1/Stardust

Tight Junction Protein Par6 Interacts with an Evolutionarily Conserved Region in the Amino Terminus of PALS1/Stardust

Identification of Multiple Binding Partners for the Amino-terminal Domain of Synapse-associated Protein 97

A General Model for Preferential Hetero-oligomerization of LIN-2/7 Domains

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