InterPro: IPR017855 SMAD domain-like

This entry represents SMAD (Mothers against decapentaplegic (MAD) homolog) (also called MH2 for MAD homology 2) domains as well as their structural homologues, such as the transactivation domain of interferon regulatory protein 3 (IRF3), both of which have a beta-sandwich structural fold.

SMAD domains are found at the carboxy terminus of MAD related proteins such as Smads. SMAD (Mothers against decapentaplegic (MAD) homolog) domain proteins are found in a range of species from nematodes to humans. These highly conserved proteins contain an N-terminal MH1 domain that contacts DNA, and is separated by a short linker region from the C-terminal MH2 domain, the later showing a striking similarity to FHA domains. SMAD proteins mediate signalling by the TGF-beta/activin/BMP-2/4 cytokines from receptor Ser/Thr protein kinases at the cell surface to the nucleus. SMAD proteins fall into three functional classes: the receptor-regulated SMADs (R-SMADs), including SMAD1, -2, -3, -5, and -8, each of which is involved in a ligand-specific signalling pathway [1]; the comediator SMADs (co-SMADs), including SMAD4, which interact with R-SMADs to participate in signalling [2]; and the inhibitory SMADs (I-SMADs), including SMAD6 and -7, which block the activation of R-SMADs and Co-SMADs, thereby negatively regulating signalling pathways [3].