STRAP

STRAP is a 38.5 kDa, 350-amino acid protein belonging to the WD40 repeat protein family. It contains seven WD40 repeats that fold into a seven-bladed β-propeller structure that spans almost the entire length of the protein. The N-terminal WD40 repeats binds to TGF-β receptor I, whereas the C-terminal region is phosphorylated by TGF-β receptor II.

STRAP is a WD40-repeat protein that binds both the type I and type II TGF-β receptors. Its primary function is to recruit and stabilize the inhibitory Smad, SMAD7, at the activated TGF-β receptor complex.

By stabilizing this STRAP/SMAD7/TGF-β receptor complex, STRAP sterically blocks SMAD2 and SMAD3 from binding to the activated type I TGF-β receptor, preventing its phosphorylation and thus blunting TGF-β mediated up-regulation of gene expression.

STRAP binds directly to ASK1 through ASK1's C-terminal domain and the fourth and sixth WD40 repeats of STRAP. This binding allows STRAP to be phosphorylated by ASK1, and the resulting complex reduces ASK1's downstream signaling to the JNK and p38 stress-response pathways. It does so by helping to stabilize ASK1's association with its own inhibitory proteins, thioredoxin and 14-3-3. It also reduces ASK1's ability to form a complex with its downstream target MKK3. Through this mechanism, STRAP protects cells from H₂O₂-induced, ASK1-driven apoptosis, favoring cell survival. STRAP has also been described as a positive regulator of PDK1 signaling.

STRAP is a component of the survival motor neuron (SMN) complex, binding to it through an interaction with GEMIN7. Loss of the complex's core protein, SMN, causes spinal muscular atrophy, a childhood disorder characterized by motor neuron degeneration.

STRAP also inhibits TGF-β receptor signaling by stabilizing the inhibitory protein SMAD7, which in turn limits activation of SMAD2 and SMAD3. This pathway is frequently dysregulated in cancer and elevated STRAP expression has been reported in several tumor types, including colorectal and lung carcinoma, where it promotes proliferation and reduces apoptosis.

STRAP has been shown to interact with:

• Mothers against decapentaplegic homolog 2,
• Mothers against decapentaplegic homolog 3,
• Mothers against decapentaplegic homolog 6,
• Mothers against decapentaplegic homolog 7,
• TGF beta receptor 1, and
• TGF beta receptor 2.