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10.1074/jbc.M113.529461 http://scihub22266oqcxt.onion/10.1074/jbc.M113.529461 C4140275!4140275 !24831002     free     free     free Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 267.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 267.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 267.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Warning: imagejpeg(C:\Inetpub\vhosts\kidney.de\httpdocs\phplern\24831002 .jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117       J+Biol+Chem 2014 ; 289 (26 ): 18137-51 Nephropedia Template TP {{tp|p=24831002 |t=2014. Lys-63-linked ubiquitination by E3 ubiquitin ligase Nedd4-1 facilitates endosomal sequestration of internalized ?-synuclein |pdf=|usr=}}{{24831002 }} gab.com Text Lys-63-linked ubiquitination by E3 ubiquitin ligase Nedd4-1 facilitates endosomal sequestration of internalized -synuclein JO: J Biol Chem http://www.kidney.de/pget.php?&tw=1&pmid=24831002 #FOAvip ?-Synuclein (aS) is a major constituent of Lewy bodies, which are not only a pathological marker for Parkinson disease but also a trigger for neurodegeneration. Cumulative evidence suggests that aS spreads from cell to cell and thereby propagates neurodegeneration to neighboring cells. Recently, Nedd4-1 (neural precursor cell expressed developmentally down-regulated protein 4-1), an E3 ubiquitin ligase, was shown to catalyze the Lys-63-linked polyubiquitination of intracellular aS and thereby facilitate aS degradation by the endolysosomal pathway. Because Nedd4-1 exerts its activity in close proximity to the inner leaflet of the plasma membrane, we speculate that after the internalization of aS the membrane resident aS is preferentially ubiquitinated by Nedd4-1. To clarify the role of Nedd4-1 in aS internalization and endolysosomal sequestration, we generated aS mutants, including ?PR1(1-119 and 129-140), ?C(1-119), and ?PR2(1-119 and 134-140), that lack the proline-rich sequence, a putative Nedd4-1 recognition site. We show that wild type aS, but not ?PR1, ?PR2, or ?C aS, is modified by Nedd4-1 in vitro, acquiring a Lys-63-linked ubiquitin chain. Compared with the mutants lacking the proline-rich sequence, wild type-aS is preferentially internalized and translocated to endosomes. The overexpression of Nedd4-1 increased aS in endosomes, whereas RNAi-mediated silencing of Nedd4-1 decreased endosomal aS. Although aS freely passes through plasma membranes within minutes, a pulse-chase experiment revealed that the overexpression of Nedd4-1 markedly decreased the re-secretion of internalized aS. Together, these findings demonstrate that Nedd4-1-linked Lys-63 ubiquitination specifies the fate of extrinsic and de novo synthesized aS by facilitating their targeting to endosomes. Twit Text FOAVip Lys-63-linked ubiquitination by E3 ubiquitin ligase Nedd4-1 facilitates endosomal sequestration of internalized -synuclein ????J Biol Chem http://www.kidney.de/pget.php?&tw=1&pmid=24831002 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=24831002 #FOAvip English Wikipedia <ref>{{Cite pmid|24831002 }}</ref> Lys-63-linked ubiquitination by E3 ubiquitin ligase Nedd4-1 facilitates endosomal sequestration of internalized ?-synuclein #MMPMID24831002 Sugeno N ; Hasegawa T ; Tanaka N ; Fukuda M ; Wakabayashi K ; Oshima R ; Konno M ; Miura E ; Kikuchi A ; Baba T ; Anan T ; Nakao M ; Geisler S ; Aoki M ; Takeda A J Biol Chem 2014[Jun]; 289 (26 ): 18137-51 PMID24831002 show ga ?-Synuclein (aS) is a major constituent of Lewy bodies, which are not only a pathological marker for Parkinson disease but also a trigger for neurodegeneration. Cumulative evidence suggests that aS spreads from cell to cell and thereby propagates neurodegeneration to neighboring cells. Recently, Nedd4-1 (neural precursor cell expressed developmentally down-regulated protein 4-1), an E3 ubiquitin ligase, was shown to catalyze the Lys-63-linked polyubiquitination of intracellular aS and thereby facilitate aS degradation by the endolysosomal pathway. Because Nedd4-1 exerts its activity in close proximity to the inner leaflet of the plasma membrane, we speculate that after the internalization of aS the membrane resident aS is preferentially ubiquitinated by Nedd4-1. To clarify the role of Nedd4-1 in aS internalization and endolysosomal sequestration, we generated aS mutants, including ?PR1(1-119 and 129-140), ?C(1-119), and ?PR2(1-119 and 134-140), that lack the proline-rich sequence, a putative Nedd4-1 recognition site. We show that wild type aS, but not ?PR1, ?PR2, or ?C aS, is modified by Nedd4-1 in vitro, acquiring a Lys-63-linked ubiquitin chain. Compared with the mutants lacking the proline-rich sequence, wild type-aS is preferentially internalized and translocated to endosomes. The overexpression of Nedd4-1 increased aS in endosomes, whereas RNAi-mediated silencing of Nedd4-1 decreased endosomal aS. Although aS freely passes through plasma membranes within minutes, a pulse-chase experiment revealed that the overexpression of Nedd4-1 markedly decreased the re-secretion of internalized aS. Together, these findings demonstrate that Nedd4-1-linked Lys-63 ubiquitination specifies the fate of extrinsic and de novo synthesized aS by facilitating their targeting to endosomes. |Amino Acid Motifs [MESH] |Cell Line, Tumor [MESH] |Endosomal Sorting Complexes Required for Transport/genetics/*metabolism [MESH] |Endosomes/genetics/*metabolism [MESH] |Humans [MESH] |Lysine/genetics/*metabolism [MESH] |Nedd4 Ubiquitin Protein Ligases [MESH] |Parkinson Disease/genetics/metabolism [MESH] |Protein Transport [MESH] |Ubiquitin-Protein Ligases/genetics/*metabolism [MESH] |Ubiquitination [MESH]Lys-63-linked ubiquitination by E3 ubiquitin ligase Nedd4-1 facilitate(epmc).pdf DeepDyve Pubget Overpricing