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Accueil > Départements > Biochimie, Biophysique et Biologie Structurale > Françoise OCHSENBEIN & Raphaël GUEROIS : Assemblage moléculaire et intégrité du génome

pubmed : ochsenbein, francois...

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NCBI : db=pubmed ; Term=Ochsenbein, Francoise[Full Author Name] or Guerois, Raphael[Full Author Name] or Andreani, Jessica[Full Author Name] or Plançon, Laure[Full Author Name]

Articles syndiqués

  • Structural plasticity of the N-terminal capping helix of the TPR domain of kinesin light chain.

    17 octobre, par Nguyen TQ, Chenon M, Vilela F, Velours C, Aumont-Nicaise M, Andreani J, Varela PF, Llinas P, Ménétrey J

    Structural plasticity of the N-terminal capping helix of the TPR domain of kinesin light chain.

    PLoS One. 2017;12(10):e0186354

    Authors: Nguyen TQ, Chenon M, Vilela F, Velours C, Aumont-Nicaise M, Andreani J, Varela PF, Llinas P, Ménétrey J

    Abstract
    Kinesin1 plays a major role in neuronal transport by recruiting many different cargos through its kinesin light chain (KLC). Various structurally unrelated cargos interact with the conserved tetratricopeptide repeat (TPR) domain of KLC. The N-terminal capping helix of the TPR domain exhibits an atypical sequence and structural features that may contribute to the versatility of the TPR domain to bind different cargos. We determined crystal structures of the TPR domain of both KLC1 and KLC2 encompassing the N-terminal capping helix and show that this helix exhibits two distinct and defined orientations relative to the rest of the TPR domain. Such a difference in orientation gives rise, at the N-terminal part of the groove, to the formation of one hydrophobic pocket, as well as to electrostatic variations at the groove surface. We present a comprehensive structural analysis of available KLC1/2-TPR domain structures that highlights that ligand binding into the groove can be specific of one or the other N-terminal capping helix orientations. Further, structural analysis reveals that the N-terminal capping helix is always involved in crystal packing contacts, especially in a TPR1:TPR1' contact which highlights its propensity to be a protein-protein interaction site. Together, these results underline that the structural plasticity of the N-terminal capping helix might represent a structural determinant for TPR domain structural versatility in cargo binding.

    PMID: 29036226 [PubMed - in process]

  • Mutations in the netrin-1 gene cause congenital mirror movements.

    26 septembre, par Méneret A, Franz EA, Trouillard O, Oliver TC, Zagar Y, Robertson SP, Welniarz Q, Gardner RJM, Gallea C, Srour M, Depienne C, Jasoni CL, Dubacq C, Riant F, Lamy JC, Morel MP, Guérois R, Andreani J, Fouquet C, Doulazmi M, Vidailhet M, Rouleau GA, Brice A, Chédotal A, Dusart I, Roze E, Markie D

    Mutations in the netrin-1 gene cause congenital mirror movements.

    J Clin Invest. 2017 Sep 25;:

    Authors: Méneret A, Franz EA, Trouillard O, Oliver TC, Zagar Y, Robertson SP, Welniarz Q, Gardner RJM, Gallea C, Srour M, Depienne C, Jasoni CL, Dubacq C, Riant F, Lamy JC, Morel MP, Guérois R, Andreani J, Fouquet C, Doulazmi M, Vidailhet M, Rouleau GA, Brice A, Chédotal A, Dusart I, Roze E, Markie D

    Abstract
    Netrin-1 is a secreted protein that was first identified 20 years ago as an axon guidance molecule that regulates midline crossing in the CNS. It plays critical roles in various tissues throughout development and is implicated in tumorigenesis and inflammation in adulthood. Despite extensive studies, no inherited human disease has been directly associated with mutations in NTN1, the gene coding for netrin-1. Here, we have identified 3 mutations in exon 7 of NTN1 in 2 unrelated families and 1 sporadic case with isolated congenital mirror movements (CMM), a disorder characterized by involuntary movements of one hand that mirror intentional movements of the opposite hand. Given the diverse roles of netrin-1, the absence of manifestations other than CMM in NTN1 mutation carriers was unexpected. Using multimodal approaches, we discovered that the anatomy of the corticospinal tract (CST) is abnormal in patients with NTN1-mutant CMM. When expressed in HEK293 or stable HeLa cells, the 3 mutated netrin-1 proteins were almost exclusively detected in the intracellular compartment, contrary to WT netrin-1, which is detected in both intracellular and extracellular compartments. Since netrin-1 is a diffusible extracellular cue, the pathophysiology likely involves its loss of function and subsequent disruption of axon guidance, resulting in abnormal decussation of the CST.

    PMID: 28945198 [PubMed - as supplied by publisher]

  • Regulation of the Human Phosphatase PTPN4 by the inter-domain linker connecting the PDZ and the phosphatase domains.

    13 août, par Caillet-Saguy C, Toto A, Guerois R, Maisonneuve P, di Silvio E, Sawyer K, Gianni S, Wolff N
    Related Articles

    Regulation of the Human Phosphatase PTPN4 by the inter-domain linker connecting the PDZ and the phosphatase domains.

    Sci Rep. 2017 Aug 11;7(1):7875

    Authors: Caillet-Saguy C, Toto A, Guerois R, Maisonneuve P, di Silvio E, Sawyer K, Gianni S, Wolff N

    Abstract
    Human protein tyrosine phosphatase non-receptor type 4 (PTPN4) has been shown to prevent cell death. The active form of human PTPN4 consists of two globular domains, a PDZ (PSD-95/Dlg/ZO-1) domain and a phosphatase domain, tethered by a flexible linker. Targeting its PDZ domain abrogates this protection and triggers apoptosis. We previously demonstrated that the PDZ domain inhibits the phosphatase activity of PTPN4 and that the mere binding of a PDZ ligand is sufficient to release the catalytic inhibition. We demonstrate here that the linker connecting the PDZ domain and the phosphatase domain is involved in the regulation of the phosphatase activity in both PDZ-related inhibition and PDZ ligand-related activation events. We combined bioinformatics and kinetic studies to decipher the role of the linker in the PTPN4 activity. By comparing orthologous sequences, we identified a conserved patch of hydrophobic residues in the linker. We showed that mutations in this patch affect the regulation of the PTPN4 bidomain indicating that the PDZ-PDZ ligand regulation of PTPN4 is a linker-mediated mechanism. However, the mutations do not alter the binding of the PDZ ligand. This study strengthens the notion that inter-domain linker can be of functional importance in enzyme regulation of large multi-domain proteins.

    PMID: 28801650 [PubMed - in process]