Urlaub H

References (6)

Title : Region-Specific Phosphorylation Determines Neuroligin-3 Localization to Excitatory versus Inhibitory Synapses - Altas_2023_Biol.Psychiatry__
Author(s) : Altas B , Tuffy LP , Patrizi A , Dimova K , Soykan T , Brandenburg C , Romanowski AJ , Whitten JR , Robertson CD , Khim SN , Crutcher GW , Ambrozkiewicz MC , Yagensky O , Krueger-Burg D , Hammer M , Hsiao HH , Laskowski PR , Dyck L , Puche AC , Sassoe-Pognetto M , Chua JJE , Urlaub H , Jahn O , Brose N , Poulopoulos A
Ref : Biological Psychiatryry , : , 2023
Abstract : BACKGROUND: Neuroligin-3 is a postsynaptic adhesion molecule involved in synapse development and function. It is implicated in rare, monogenic forms of autism, and its shedding is critical to the tumor microenvironment of gliomas. While other members of the Neuroligin family exhibit synapse-type specificity in localization and function through distinct interactions with postsynaptic scaffold proteins, the specificity of Neuroligin-3 synaptic localization remains largely unknown. METHODS: We investigated the synaptic localization of Neuroligin-3 across regions in mouse and human brain samples after validating antibody specificity in knockout animals. We raised a phospho-specific Neuroligin antibody and used phosphoproteomics, cell-based assays, and in utero CRISPR/Cas9 knockout and gene replacement to identify mechanisms that regulate Neuroligin-3 localization to distinct synapse types. RESULTS: Neuroligin-3 exhibits region-dependent synapse specificity, largely localizing to excitatory synapses in cortical regions and inhibitory synapses in subcortical regions of the brain in both mice and humans. We identified specific phosphorylation of cortical Neuroligin-3 at a key binding site for recruitment to inhibitory synapses, while subcortical Neuroligin-3 remained unphosphorylated. In vitro, phosphomimetic mutation of that site disrupted Neuroligin-3 association with the inhibitory postsynaptic scaffolding protein, Gephyrin. In vivo, phosphomimetic mutants of Neuroligin-3 localized to excitatory postsynapses, while phospho-null mutants localized to inhibitory postsynapses. CONCLUSIONS: These data reveal an unexpected region-specific pattern of Neuroligin-3 synapse specificity, as well as a phosphorylation-dependent mechanism that regulates its recruitment to either excitatory or inhibitory synapses. These findings add to our understanding of how Neuroligin-3 is involved in conditions that may affect the balance of excitation and inhibition.
ESTHER : Altas_2023_Biol.Psychiatry__
PubMedSearch : Altas_2023_Biol.Psychiatry__
PubMedID: 38154503
Gene_locus related to this paper: human-NLGN3 , mouse-3neur

Title : Dipeptidyl peptidase 9 triggers BRCA2 degradation and promotes DNA damage repair - Bolgi_2022_EMBO.Rep__e54136
Author(s) : Bolgi O , Silva-Garcia M , Ross B , Pilla E , Kari V , Killisch M , Spitzner M , Stark N , Lenz C , Weiss K , Donzelli L , Gorrell MD , Grade M , Riemer J , Urlaub H , Dobbelstein M , Huber R , Geiss-Friedlander R
Ref : EMBO Rep , :e54136 , 2022
Abstract : N-terminal sequences are important sites for post-translational modifications that alter protein localization, activity, and stability. Dipeptidyl peptidase 9 (DPP9) is a serine aminopeptidase with the rare ability to cleave off N-terminal dipeptides with imino acid proline in the second position. Here, we identify the tumor-suppressor BRCA2 as a DPP9 substrate and show this interaction to be induced by DNA damage. We present crystallographic structures documenting intracrystalline enzymatic activity of DPP9, with the N-terminal Met1-Pro2 of a BRCA21-40 peptide captured in its active site. Intriguingly, DPP9-depleted cells are hypersensitive to genotoxic agents and are impaired in the repair of DNA double-strand breaks by homologous recombination. Mechanistically, DPP9 targets BRCA2 for degradation and promotes the formation of RAD51 foci, the downstream function of BRCA2. N-terminal truncation mutants of BRCA2 that mimic a DPP9 product phenocopy reduced BRCA2 stability and rescue RAD51 foci formation in DPP9-deficient cells. Taken together, we present DPP9 as a regulator of BRCA2 stability and propose that by fine-tuning the cellular concentrations of BRCA2, DPP9 alters the BRCA2 interactome, providing a possible explanation for DPP9's role in cancer.
ESTHER : Bolgi_2022_EMBO.Rep__e54136
PubMedSearch : Bolgi_2022_EMBO.Rep__e54136
PubMedID: 35912982
Gene_locus related to this paper: human-DPP8 , human-DPP9

Title : Dipeptidyl peptidase 9 triggers BRCA2 degradation by the N-degron pathway to promote DNA-damage repair - Silva-Garcia_2020_Biorxiv__
Author(s) : Silva-Garcia M , Bolgi O , Ross B , Pilla E , Kari V , Killisch M , Stark N , Lenz C , Spitzner M , Gorrell MD , Grade M , Urlaub H , Dobbelstein M , Huber R , Geiss-Friedlander R
Ref : Biorxiv , : , 2020
Abstract : Dipeptidyl peptidase 9 (DPP9) is a serine protease cleaving N-terminal dipeptides preferentially post-proline with (patho)physiological roles in the immune system and cancer. Only few DPP9 substrates are known. Here we identify an association of human DPP9 with the tumour suppressor BRCA2, a key player in repair of DNA double-strand breaks that promotes the formation of RAD51 filaments. This interaction is triggered by DNA-damage and requires access to the DPP9 active-site. We present crystallographic structures documenting the N-terminal Met1-Pro2 of a BRCA21-40 peptide captured in the DPP9 active-site. Mechanistically, DPP9 targets BRCA2 for degradation by the N-degron pathway, and promotes RAD51 foci formation. Both processes are phenocopied by BRCA2 N-terminal truncation mutants, indicating that DPP9 regulates both stability and the cellular stoichiometric interactome of BRCA2. Consistently, DPP9-deprived cells are hypersensitive to DNA-damage. Together, we identify DPP9 as a regulator of BRCA2, providing a possible explanation for DPP9 involvement in cancer development.
ESTHER : Silva-Garcia_2020_Biorxiv__
PubMedSearch : Silva-Garcia_2020_Biorxiv__
PubMedID:
Gene_locus related to this paper: human-DPP8 , human-DPP9

Title : DPP9 is a novel component of the N-end rule pathway targeting the tyrosine kinase Syk - Justa-Schuch_2016_Elife_5_
Author(s) : Justa-Schuch D , Silva-Garcia M , Pilla E , Engelke M , Kilisch M , Lenz C , Moller U , Nakamura F , Urlaub H , Geiss-Friedlander R
Ref : Elife , 5 : , 2016
Abstract : The aminopeptidase DPP9 removes dipeptides from N-termini of substrates having a proline or alanine in second position. Although linked to several pathways including cell survival and metabolism, the molecular mechanisms underlying these outcomes are poorly understood. We identified a novel interaction of DPP9 with Filamin A, which recruits DPP9 to Syk, a central kinase in B-cell signalling. Syk signalling can be terminated by degradation, requiring the ubiquitin E3 ligase Cbl. We show that DPP9 cleaves Syk to produce a neo N-terminus with serine in position 1. Pulse-chases combined with mutagenesis studies reveal that Ser1 strongly influences Syk stability. Furthermore, DPP9 silencing reduces Cbl interaction with Syk, suggesting that DPP9 processing is a prerequisite for Syk ubiquitination. Consistently, DPP9 inhibition stabilizes Syk, thereby modulating Syk signalling. Taken together, we demonstrate DPP9 as a negative regulator of Syk and conclude that DPP9 is a novel integral aminopeptidase of the N-end rule pathway.
ESTHER : Justa-Schuch_2016_Elife_5_
PubMedSearch : Justa-Schuch_2016_Elife_5_
PubMedID: 27614019

Title : The SUMO1-E67 Interacting Loop Peptide Is an Allosteric Inhibitor of the Dipeptidyl Peptidases 8 and 9 - Pilla_2013_J.Biol.Chem_288_32787
Author(s) : Pilla E , Kilisch M , Lenz C , Urlaub H , Geiss-Friedlander R
Ref : Journal of Biological Chemistry , 288 :32787 , 2013
Abstract : The intracellular peptidases dipeptidyl peptidase (DPP) 8 and DPP9 are involved in multiple cellular pathways including antigen maturation, cellular homeostasis, energy metabolism, and cell viability. Previously we showed that the small ubiquitin-like protein modifier SUMO1 interacts with an armlike structure in DPP9, leading to allosteric activation of the peptidase. Here we demonstrate that the E67-interacting loop (EIL) peptide, which corresponds to the interaction surface of SUMO1 with DPP9, acts as a noncompetitive inhibitor of DPP9. Moreover, by analyzing the sensitivity of DPP9 arm mutants to the EIL peptide, we mapped specific residues in the arm that are important for inhibition by the EIL, suggesting that the peptide acts as an allosteric inhibitor of DPP9. By modifying the EIL peptide, we constructed peptide variants with more than a 1,000-fold selectivity toward DPP8 (147 nm) and DPP9 (170 nm) over DPPIV (200 mum). Furthermore, application of these peptides to cells leads to a clear inhibition of cellular prolyl peptidase activity. Importantly, in line with previous publications, inhibition of DPP9 with these novel allosteric peptide inhibitors leads to an increase in EGF-mediated phosphorylation of Akt. This work highlights the potential use of peptides that mimic interaction surfaces for modulating enzyme activity.
ESTHER : Pilla_2013_J.Biol.Chem_288_32787
PubMedSearch : Pilla_2013_J.Biol.Chem_288_32787
PubMedID: 24072711
Gene_locus related to this paper: human-DPP8 , human-DPP9

Title : The cytoplasmic peptidase DPP9 is rate-limiting for degradation of proline-containing peptides - Geiss-Friedlander_2009_J.Biol.Chem_284_27211
Author(s) : Geiss-Friedlander R , Parmentier N , Moller U , Urlaub H , Van den Eynde BJ , Melchior F
Ref : Journal of Biological Chemistry , 284 :27211 , 2009
Abstract : Protein degradation is an essential process that continuously takes place in all living cells. Regulated degradation of most cellular proteins is initiated by proteasomes, which produce peptides of varying length. These peptides are rapidly cleaved to single amino acids by cytoplasmic peptidases. Proline-containing peptides pose a specific problem due to structural constrains imposed by the pyrrolidine ring that prevents most peptidases from cleavage. Here we show that DPP9, a poorly characterized cytoplasmic prolyl-peptidase, is rate-limiting for destruction of proline-containing substrates both in cell extracts and in intact cells. We identified the first natural substrate for DPP9, the RU1(34-42) antigenic peptide (VPYGSFKHV). RU1(34-42) is degraded in vitro by DPP9, and down-regulation of DPP9 in intact cells results in increased presentation of this antigen. Together our findings demonstrate an important role for DPP9 in peptide turnover and antigen presentation.
ESTHER : Geiss-Friedlander_2009_J.Biol.Chem_284_27211
PubMedSearch : Geiss-Friedlander_2009_J.Biol.Chem_284_27211
PubMedID: 19667070
Gene_locus related to this paper: human-DPP9