Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair.
Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair.
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DOI：
10.1038/ng.425
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发表时间：
2009-09
期刊：
影响因子：
30.8
通讯作者：
Tartaglia, Marco
中科院分区：
文献类型：
--
作者：
Cordeddu, Viviana;Di Schiavi, Elia;Pennacchio, Len A.;Ma'ayan, Avi;Sarkozy, Anna;Fodale, Valentina;Cecchetti, Serena;Cardinale, Alessio;Martin, Joel;Schackwitz, Wendy;Lipzen, Anna;Zampino, Giuseppe;Mazzanti, Laura;Digilio, Maria C.;Martinelli, Simone;Flex, Elisabetta;Lepri, Francesca;Bartholdi, Deborah;Kutsche, Kerstin;Ferrero, Giovanni B.;Anichini, Cecilia;Selicorni, Angelo;Rossi, Cesare;Tenconi, Romano;Zenker, Martin;Merlo, Daniela;Dallapiccola, Bruno;Iyengar, Ravi;Bazzicalupo, Paolo;Gelb, Bruce D.;Tartaglia, Marco
肉豆蔻酰化是一种常见的共翻译蛋白质脂肪酰化形式，由肉豆蔻酸酯与所需的N-末端甘氨酸残基连接而成。我们发现，SHOC2是一种富含亮氨酸重复序列的蛋白，它积极地调节Ras-MAPK信号流，其异常获得的N-肉豆蔻酸化是神经-心脏-面部-皮肤疾病家族临床上独特的疾病的基础。25名表型相对一致的受试者以前被称为Noonan样综合征伴生长期头发稀疏[OMIM 607721]，他们共享SHOC2的4A&>G错义改变(Ser2Gly)，该错义改变引入了N-肉豆蔻酰化位点，导致SHOC2异常靶向质膜，并在生长因子刺激下阻碍移位到细胞核。SHOC2S2G在体外的表达以一种细胞类型特异性的方式促进MAPK的激活。在秀丽线虫中诱导SHOC2S2G产生突出的外阴，这是一种以前与异常信号相关的新表型。这些结果证明了导致人类疾病的蛋白质的获得性N末端脂质修饰的第一个例子。
N-myristoylation is a common form of co-translational protein fatty acylation resulting from the attachment of myristate to a required N-terminal glycine residue. We show that aberrantly acquired N-myristoylation of SHOC2, a leucine-rich repeat-containing protein that positively modulates RAS-MAPK signal flow, underlies a clinically distinctive condition of the neuro-cardio-facial-cutaneous disorders family. Twenty-five subjects with a relatively consistent phenotype previously termed Noonan-like syndrome with loose anagen hair [OMIM 607721] shared the 4A>G missense change (Ser2Gly) in SHOC2 that introduces an N-myristoylation site, resulting in aberrant targeting of SHOC2 to the plasma membrane and impaired translocation to the nucleus upon growth factor stimulation. Expression of SHOC2S2G in vitro enhanced MAPK activation in a cell type-specific fashion. Induction of SHOC2S2G in Caenorhabditis elegans engendered protruding vulva, a neomorphic phenotype previously associated with aberrant signaling. These results document the first example of an acquired N-terminal lipid modification of a protein causing human disease.
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影响因子：
3
作者：
Berger SI;Posner JM;Ma'ayan A
通讯作者：
Ma'ayan A
影响因子：
2.7
作者：
Kishore, RS;Sundaram, MV
通讯作者：
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影响因子：
30.8
作者：
Tartaglia, Marco;Pennacchio, Len A.;Gelb, Bruce D.
通讯作者：
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影响因子：
14.9
作者：
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通讯作者：
Cesareni, Gianni
影响因子：
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作者：
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通讯作者：
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