Structural characterization of the third scavenger receptor cysteine‐rich domain of murine neurotrypsin

Canciani, Anselmo; Catucci, Gianluca; Forneris, Federico

doi:10.1002/pro.3587

Cited by 9 publications

(21 citation statements)

References 52 publications

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“…This reveals a highly conserved fold across both type A and type B SRCR domains. SRCR1 (pale green), SRCR8 (light blue), MARCO (pdbid: 2oy3, sand), CD163 (pdbid: 5jfb, purple), CD5 (pdbid: 2OTT, grey), CD6 (pdbid: 5a2e, pink), M2bp (pdbid: 1by2, yellow), and murine neurotrypsin (pdbid: 6h8m, teal)(35). SALSA magnesium: green, MARCO magnesium: blue.…”

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confidence: 99%

Structures of SALSA/DMBT1 SRCR domains reveal the conserved ligand-binding mechanism of the ancient SRCR fold

et al. 2020

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The scavenger receptor cysteine-rich (SRCR) family of proteins comprises more than 20 membrane-associated and secreted molecules. Characterised by the presence of one or more copies of the ∼110 amino-acid SRCR domain, this class of proteins have widespread functions as antimicrobial molecules, scavenger receptors, and signalling receptors. Despite the high level of structural conservation of SRCR domains, no unifying mechanism for ligand interaction has been described. The SRCR protein SALSA, also known as DMBT1/gp340, is a key player in mucosal immunology. Based on detailed structural data of SALSA SRCR domains 1 and 8, we here reveal a novel universal ligand-binding mechanism for SALSA ligands. The binding interface incorporates a dual cation-binding site, which is highly conserved across the SRCR superfamily. Along with the well-described cation dependency on most SRCR domain–ligand interactions, our data suggest that the binding mechanism described for the SALSA SRCR domains is applicable to all SRCR domains. We thus propose to have identified in SALSA a conserved functional mechanism for the SRCR class of proteins.

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confidence: 99%

Structures of SALSA/DMBT1 SRCR domains reveal the conserved ligand-binding mechanism of the ancient SRCR fold

et al. 2020

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“…This reveals a highly conserved fold across both type A and type B SRCR domains. SRCR1 (pale green), SRCR8MgCa (light blue), MARCO (pdbid: 2oy3, sand), CD163 (pdbid: 5jfb, purple), CD5 (pdbid: 2OTT, grey), CD6 (pdbid: 5a2e, pink), M2bp (pdbid: 1by2, yellow), and murine neurotrypsin (pdbid: 6h8m, teal) [38]. SALSA Magnesium: dark green, MARCO Magnesium: red, Calcium: dark purple.…”

Section: Resultsmentioning

confidence: 99%

The structure of SALSA/DMBT1 SRCR domains reveal the conserved ligand-binding mechanism of the ancient SRCR-fold

Reichhardt

Loimaranta

Lea

et al. 2019

Preprint

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The scavenger receptor cysteine-rich (SRCR) family of proteins comprise more than 20 membrane-associated and secreted molecules. Characterised by the presence of one or more copies of the ~110 amino acid SRCR domain, this class of proteins have widespread functions as anti-microbial molecules, scavenger- and signalling-receptors. Despite the high level of structural conservation of SRCR domains, no molecular basis for ligand interaction has been described. The SRCR protein SALSA, also known as dmbt1/gp340, is a key player in mucosal immunology. Based on detailed structures of the SALSA SRCR domains 1 and 8, we here reveal a novel universal ligand binding mechanism for SALSA ligands. The binding interface incorporates a dual cation binding site, which is highly conserved across the SRCR super family. Along with the well-described cation dependency on most SRCR domain-ligand interactions, our data suggest that the binding mechanism described for the SALSA SRCR domains is applicable to all SRCR domains. We thus propose to have identified in SALSA a conserved functional mechanism for ligand recognition by the SRCR class of proteins.

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“…Additional secondary agrin:agrin and agrin:LRP4 contact points are highlighted in blue and yellow, respectively. domain of the human protein seems to be absent in mice (Proba et al, 1998;Canciani et al, 2019).…”

Section: Neurotrypsin: Agrin's Regulatory Proteasementioning

confidence: 95%

“…Knowledge pertaining to NTs structural organization is limited (Figure 6), as only the structures for the N-terminal Kr domain (Ozhogina et al, 2008) and the C-terminal SRCR domain (Canciani et al, 2019) proximate to the SP domain have been described. The former has been attributed with no specific function beyond a putative binding to the product of seizure related gene 6 (Mitsui et al, 2013).…”

Section: Neurotrypsin: Agrin's Regulatory Proteasementioning

confidence: 99%

“…Similarly, precious little has been reported, so far, pertaining to the functional role of NT's SRCR domains. Realistically, these are likely to mediate protein-target interactions, and/or contribute to Ca 2+ binding (Martinez et al, 2011;Canciani et al, 2019). Interestingly, in other proteins of the SRCR domain-bearing superfamily several domains of this type have been attributed with a Ca2 + dependant ligand recognition/binding function (Sarrias et al, 2005(Sarrias et al, , 2007Ojala et al, 2007;Reichhardt et al, 2019).…”

Section: Neurotrypsin: Agrin's Regulatory Proteasementioning

confidence: 99%

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Dissecting the Extracellular Complexity of Neuromuscular Junction Organizers

Guarino

Canciani

Forneris

2020

Front. Mol. Biosci.

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Synapse formation is a very elaborate process dependent upon accurate coordination of pre and post-synaptic specialization, requiring multiple steps and a variety of receptors and signaling molecules. Due to its relative structural simplicity and the ease in manipulation and observation, the neuromuscular synapse or neuromuscular junction (NMJ)-the connection between motor neurons and skeletal muscle-represents the archetype junction system for studying synapse formation and conservation. This junction is essential for survival, as it controls our ability to move and breath. NMJ formation requires coordinated interactions between motor neurons and muscle fibers, which ultimately result in the formation of a highly specialized post-synaptic architecture and a highly differentiated nerve terminal. Furthermore, to ensure a fast and reliable synaptic transmission following neurotransmitter release, ligand-gated channels (acetylcholine receptors, AChRs) are clustered on the post-synaptic muscle cell at high concentrations in sites opposite the presynaptic active zone, supporting a direct role for nerves in the organization of the post-synaptic membrane architecture. This organized clustering process, essential for NMJ formation and for life, relies on key signaling molecules and receptors and is regulated by soluble extracellular molecules localized within the synaptic cleft. Notably, several mutations as well as auto-antibodies against components of these signaling complexes have been related to neuromuscular disorders. The recent years have witnessed strong progress in the understanding of molecular identities, architectures, and functions of NMJ macromolecules. Among these, prominent roles have been proposed for neural variants of the proteoglycan agrin, its receptor at NMJs composed of the lipoprotein receptor-related protein 4 (LRP4) and the muscle-specific kinase (MuSK), as well as the regulatory soluble synapse-specific protease Neurotrypsin. In this review we summarize the current state of the art regarding molecular structures and (agrin-dependent) canonical, as well as (agrin-independent) non-canonical, MuSK signaling mechanisms that underscore the formation of neuromuscular junctions, with the aim of providing a broad perspective to further stimulate molecular, cellular and tissue biology investigations on this fundamental intercellular contact.

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Structural characterization of the third scavenger receptor cysteine‐rich domain of murine neurotrypsin

Cited by 9 publications

References 52 publications

Structures of SALSA/DMBT1 SRCR domains reveal the conserved ligand-binding mechanism of the ancient SRCR fold

Structures of SALSA/DMBT1 SRCR domains reveal the conserved ligand-binding mechanism of the ancient SRCR fold

The structure of SALSA/DMBT1 SRCR domains reveal the conserved ligand-binding mechanism of the ancient SRCR-fold

Dissecting the Extracellular Complexity of Neuromuscular Junction Organizers

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