The L45 loop in type I receptors for TGF‐β family members is a critical determinant in specifying Smad isoform activation

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Abstract
Transforming growth factor‐β (TGF‐β) and bone morphogenetic proteins (BMPs) signal via distinct type I and type II receptors and Smad proteins. A nine amino acid sequence between kinase subdomains IV and V in type I receptors, termed the L45 loop, has been shown to be important in conferring signalling specificity. We examined the responses of a mutant TGF‐β type I receptor (TβR‐I) and a mutant BMPR‐IB, in which the L45 regions of these two receptors were exchanged. Swapping the four amino acid residues that are different in BMPR‐IB for those in TβR‐I, and vice versa, switched their type I receptor‐restricted Smad activation and specificity in transcriptional responses. These studies identify the L45 loop regions in type I receptors as critical determinants in specifying Smad isoform activation.