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10.1074/jbc.M114.562355 http://scihub22266oqcxt.onion/10.1074/jbc.M114.562355 C4047398!4047398 !24770419     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 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 Warning: imagejpeg(C:\Inetpub\vhosts\kidney.de\httpdocs\phplern\24770419 .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 (23 ): 16290-302 Nephropedia Template TP {{tp|p=24770419 |t=2014. Inefficient translocation of preproinsulin contributes to pancreatic ? cell failure and late-onset diabetes |pdf=|usr=}}{{24770419 }} gab.com Text Inefficient translocation of preproinsulin contributes to pancreatic cell failure and late-onset diabetes JO: J Biol Chem http://www.kidney.de/pget.php?&tw=1&pmid=24770419 #FOAvip Among the defects in the early events of insulin biosynthesis, proinsulin misfolding and endoplasmic reticulum (ER) stress have drawn increasing attention as causes of ? cell failure. However, no studies have yet addressed potential defects at the cytosolic entry point of preproinsulin into the secretory pathway. Here, we provide the first evidence that inefficient translocation of preproinsulin (caused by loss of a positive charge in the n region of its signal sequence) contributes to ? cell failure and diabetes. Specifically, we find that, after targeting to the ER membrane, preproinsulin signal peptide (SP) mutants associated with autosomal dominant late-onset diabetes fail to be fully translocated across the ER membrane. The newly synthesized, untranslocated preproinsulin remains strongly associated with the ER membrane, exposing its proinsulin moiety to the cytosol. Rather than accumulating in the ER and inducing ER stress, untranslocated preproinsulin accumulates in a juxtanuclear compartment distinct from the Golgi complex, induces the expression of heat shock protein 70 (HSP70), and promotes ? cell death. Restoring an N-terminal positive charge to the mutant preproinsulin SP significantly improves the translocation defect. These findings not only reveal a novel molecular pathogenesis of ? cell failure and diabetes but also provide the first evidence of the physiological and pathological significance of the SP n region positive charge of secretory proteins. Twit Text FOAVip Inefficient translocation of preproinsulin contributes to pancreatic cell failure and late-onset diabetes ????J Biol Chem http://www.kidney.de/pget.php?&tw=1&pmid=24770419 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=24770419 #FOAvip English Wikipedia <ref>{{Cite pmid|24770419 }}</ref> Inefficient translocation of preproinsulin contributes to pancreatic ? cell failure and late-onset diabetes #MMPMID24770419 Guo H ; Xiong Y ; Witkowski P ; Cui J ; Wang LJ ; Sun J ; Lara-Lemus R ; Haataja L ; Hutchison K ; Shan SO ; Arvan P ; Liu M J Biol Chem 2014[Jun]; 289 (23 ): 16290-302 PMID24770419 show ga Among the defects in the early events of insulin biosynthesis, proinsulin misfolding and endoplasmic reticulum (ER) stress have drawn increasing attention as causes of ? cell failure. However, no studies have yet addressed potential defects at the cytosolic entry point of preproinsulin into the secretory pathway. Here, we provide the first evidence that inefficient translocation of preproinsulin (caused by loss of a positive charge in the n region of its signal sequence) contributes to ? cell failure and diabetes. Specifically, we find that, after targeting to the ER membrane, preproinsulin signal peptide (SP) mutants associated with autosomal dominant late-onset diabetes fail to be fully translocated across the ER membrane. The newly synthesized, untranslocated preproinsulin remains strongly associated with the ER membrane, exposing its proinsulin moiety to the cytosol. Rather than accumulating in the ER and inducing ER stress, untranslocated preproinsulin accumulates in a juxtanuclear compartment distinct from the Golgi complex, induces the expression of heat shock protein 70 (HSP70), and promotes ? cell death. Restoring an N-terminal positive charge to the mutant preproinsulin SP significantly improves the translocation defect. These findings not only reveal a novel molecular pathogenesis of ? cell failure and diabetes but also provide the first evidence of the physiological and pathological significance of the SP n region positive charge of secretory proteins. |Amino Acid Sequence [MESH] |Animals [MESH] |Diabetes Mellitus/*metabolism/pathology [MESH] |Endoplasmic Reticulum/metabolism [MESH] |Humans [MESH] |Insulin/chemistry/*metabolism [MESH] |Islets of Langerhans/*metabolism/pathology [MESH] |Mice [MESH] |Molecular Sequence Data [MESH] |Protein Precursors/chemistry/*metabolism [MESH] |Protein Transport [MESH] |Rats [MESH]Inefficient translocation of preproinsulin contributes to pancreatic ?(epmc).pdf DeepDyve Pubget Overpricing