Rab geranylgeranyl transferase α mutation in the gunmetal mouse reduces Rab prenylation and platelet synthesis
Rab geranylgeranyl transferase α mutation in the gunmetal mouse reduces Rab prenylation and platelet synthesis
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DOI：
10.1073/pnas.080517697
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发表时间：
2000-04-11
影响因子：
11.1
通讯作者：
Kingsmore, SF
中科院分区：
文献类型：
--
作者：
Detter, JC;Zhang, Q;Kingsmore, SF
血小板生物发生的重要分子事件很少。自发隐性突变炮铜（gm）纯合子小鼠出血时间延长，血小板减少，血小板α和δ颗粒含量减少。在这里，我们通过定位克隆表明，gm的结果从G->A取代突变的一个剪接受体位点内的α-亚基的Rab香叶基香叶基转移酶（Rabggta），一种酶，重视香叶基香叶基基团的Rab蛋白。来自gm组织的大多数Rabggta mRNA跳过外显子1并且缺少起始密码子，Rabggta蛋白和Rab香叶基香叶基转移酶（GGT酶）活性在gm血小板中降低4倍。在gm血小板中，Rab 27（一种Rab GGT酶底物）的香叶基香叶基化和膜结合显著降低。这些发现表明Rab GTP酶的香叶基香叶基化对于止血至关重要。Rab GGT酶抑制可能代表血小板增多症和凝血障碍的新治疗。
Few molecular events important to platelet biogenesis have been identified. Mice homozygous for the spontaneous, recessive mutation gunmetal (gm) have prolonged bleeding, thrombocytopenia, and reduced platelet alpha- and delta-granule contents. Here we show by positional cloning that gm results from a G-->A substitution mutation in a splice acceptor site within the alpha-subunit of Rab geranylgeranyl transferase (Rabggta), an enzyme that attaches geranylgeranyl groups to Rab proteins. Most Rabggta mRNAs from gm tissues skipped exon 1 and lacked a start codon, Rabggta protein and Rab geranylgeranyl transferase (GGTase) activity were reduced 4-fold in gm platelets. Geranylgeranylation and membrane association of Rab27, a Rab GGTase substrate, were significantly decreased in gm platelets. These findings indicate that geranylgeranylation of Rab GTPases is critical for hemostasis. Rab GGTase inhibition may represent a new treatment for thrombocytosis and clotting disorders.