Verhagen A M, Kratina T K, Hawkins C J, Silke J, Ekert P G, Vaux D L
The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia.
Cell Death Differ. 2007 Feb;14(2):348-57. doi: 10.1038/sj.cdd.4402001. Epub 2006 Jun 23.
Direct IAP binding protein with low pI/second mitochondrial activator of caspases, HtrA2/Omi and GstPT/eRF3 are mammalian proteins that bind via N-terminal inhibitor of apoptosis protein (IAP) binding motifs (IBMs) to the baculoviral IAP repeat (BIR) domains of IAPs. These interactions can prevent IAPs from inhibiting caspases, or displace active caspases, thereby promoting cell death. We have identified several additional potential IAP antagonists, including glutamate dehydrogenase (GdH), Nipsnap 3 and 4, CLPX, leucine-rich pentatricopeptide repeat motif-containing protein and 3-hydroxyisobutyrate dehydrogenase. All are mitochondrial proteins from which N-terminal import sequences are removed generating N-terminal IBMs. Whereas most of these proteins have alanine at the N-terminal position, as observed for previously described antagonists, GdH has an N-terminal serine residue that is essential for X-linked IAP (XIAP) interaction. These newly described IAP binding proteins interact with XIAP mainly via BIR2, with binding eliminated or significantly reduced by a single point mutation (D214S) within this domain. Through this interaction, many are able to antagonise XIAP inhibition of caspase 3 in vitro.
低等电点直接IAP结合蛋白/半胱天冬酶的第二个线粒体激活剂、HtrA2/Omi和GstPT/eRF3是哺乳动物蛋白，它们通过N端凋亡抑制蛋白（IAP）结合基序（IBM）与IAP的杆状病毒IAP重复序列（BIR）结构域结合。这些相互作用可阻止IAP抑制半胱天冬酶，或取代活性半胱天冬酶，从而促进细胞死亡。我们已经鉴定出几种其他潜在的IAP拮抗剂，包括谷氨酸脱氢酶（GdH）、Nipsnap 3和4、CLPX、富含亮氨酸的五肽重复基序蛋白以及3-羟基异丁酸脱氢酶。所有这些都是线粒体蛋白，其N端导入序列被去除，从而产生N端IBM。正如之前描述的拮抗剂所观察到的那样，这些蛋白中的大多数在N端位置有丙氨酸，而GdH有一个N端丝氨酸残基，这对于与X连锁IAP（XIAP）的相互作用至关重要。这些新描述的IAP结合蛋白主要通过BIR2与XIAP相互作用，该结构域内的单点突变（D214S）可消除或显著降低这种结合。通过这种相互作用，许多蛋白能够在体外拮抗XIAP对半胱天冬酶3的抑制作用。
