Diablo homolog (DIABLO) is a
mitochondrialprotein that in humans is encoded by the DIABLO (direct
IAP binding protein with low pI)
gene on chromosome 12.[5][6][7] DIABLO is also referred to as second mitochondria-derived activator of caspases or SMAC. This protein binds
inhibitor of apoptosis proteins (IAPs), thus freeing
caspases to activate
apoptosis.[7][8] Due to its proapoptotic function, SMAC is implicated in a broad spectrum of tumors, and
small molecule SMAC
mimetics have been developed to enhance current cancer treatments.[7][9]
Structure
Protein
This gene encodes a 130 Å-long, arch-shaped
homodimer protein. The full-length protein product spans 239
residues, 55 of which comprise the mitochondrial-
targeting sequence (MTS) at its
N-terminal. However, once the full-length protein is imported into the mitochondria, this sequence is excised to produce the 184-residue mature protein.[9][10][11] This
cleavage also exposes four residues at the N-terminal, Ala-Val-Pro-Ile (AVPI), which is the core of the IAP binding domain and crucial for
inhibitingXIAP.[9][10][11] Specifically, the tetrapeptide sequence binds the BIR3
domain of XIAP to form a stable
complex between SMAC and XIAP.[9][10][11] The homodimer structure also facilitates SMAC-XIAP binding via the BIR2 domain, though it does not form until the protein is released into the
cytoplasm as a result of
outer mitochondrial membranepermeabilization.[11] Thus,
monomeric SMAC
mutants can still bind the BIR3 domain but not the BIR2 domain, which compromises the protein’s inhibitory function.[10] Meanwhile, mutations within the AVPI sequence lead to loss of function, though SMAC may still be able to perform IAP binding-independent functions, such as inducing the
ubiquitinylation of XIAP.[10][12]
Gene
Several
alternatively spliced transcript variants that encode distinct
isoforms have been described for this gene, but the validity of some transcripts, and their predicted
ORFs, has not been determined conclusively.[7][10] Two known isoforms both lack the MTS and the IAP binding domain, suggesting differential
subcellular localization and function.[12]
Function
SMAC is a mitochondrial protein that promotes
cytochrome c- and
TNF receptor-dependent activation of apoptosis by inhibiting the effect of IAP – a group of proteins that negatively regulate
apoptosis, or programmed cell death.[8][13] SMAC is normally a mitochondrial protein localized to the mitochondrial
intermembrane space, but it enters the
cytosol when cells undergo apoptosis.[7][10][12][14] Through the
intrinsic pathway of apoptosis,
BCL-2 proteins like
BAK and
BAX form a
pore in the
outer mitochondrial membrane, leading to mitochondrial membrane permeabilization and the release of both cytochrome c and SMAC.[9][10] While cytochrome c directly activates
APAF1 and
caspase 9, SMAC binds IAPs, such as XIAP and cIAP proteins, to inhibit their caspase-binding activity and allow for
caspase activation of apoptosis.[7][9][10][12][14] SMAC is ubiquitously expressed in many cell types, implicating it in various biological processes involving apoptosis.[15] Currently, nonapoptotic functions for SMAC remain unclear.[11]
Following experimental elucidation of SMAC structure, small-molecule SMAC
mimetics have been developed to mimic the tetrapeptide AVPI in the IAP binding domain of SMAC, which is responsible for binding the BIR3 domains in IAPs like XIAP, cIAP1, and cIAP2 to induce apoptosis, and sometimes,
necroptosis.[9][16] Several of the numerous SMAC mimetics designed within the last decade or so are now undergoing clinical trials, including SM-406 by Bai and colleagues and two mimetics by
Genentech. These mimetics are also designed to target tumor cells directly through interacting with inflammatory proteins, such as
IL-1β, which are commonly produced by
solid tumor lesions.[9] Notably, preclinical studies indicate that the use of SMAC mimetics in conjunction with
chemotherapy,
death receptorligands and
agonists, as well as
small moleculetargeted drugs enhance the sensitivity of tumor cells to these treatments.[9][13][16] In addition to improving the success of tumor elimination, this increased sensitivity can permit smaller doses, thus minimizing side effects while maintaining efficacy.[16] Nonetheless, there still exists the potential for side effects, such as elevated levels of
cytokines and
chemokines in normal tissues, depending on the cellular environment.[9]
In addition to cancers, mutations in DIABLO is associated with young-adult onset of nonsyndromic deafness-64.[7]
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^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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abcdZeng H, Zhang S, Yang KY, Wang T, Hu JL, Huang LL, Wu G (December 2010). "Knockdown of second mitochondria-derived activator of caspase expression by RNAi enhances growth and cisplatin resistance of human lung cancer cells". Cancer Biotherapy & Radiopharmaceuticals. 25 (6): 705–12.
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