The STI1‐domain is a flexible alpha‐helical fold with a hydrophobic groove

Abstract

STI1-domains are present in a variety of co-chaperone proteins and are required for the transfer of hydrophobic clients in various cellular processes. The domains were first identified in the yeast Sti1 protein where they were referred to as DP1 and DP2. Based on hidden Markov model searches, this domain had previously been found in other proteins including the mammalian co-chaperone SGTA, the DNA damage response protein Rad23, and the chloroplast import protein Tic40. Here, we refine the domain definition and carry out structure-based sequence alignment of STI1-domains showing conservation of five amphipathic helices. Upon examinations of these identified domains, we identify a preceding helix 0 and unifying sequence properties, determine new molecular models, and recognize that STI1-domains nearly always occur in pairs. The similarity at the sequence, structure, and molecular levels likely supports a unified functional role.

Alphavirus nsP2 protease structure and cleavage prediction: Possible relevance to the pathogenesis of viral arthritis

“…[105] Cleavage of ubiquilin-1 between its ubiquitin-associated (UBA) and ubiquitin-like (UBL) domains may disrupt its trafficking ubiquitinated proteins to the proteasome[106] or its targeting of transmembrane proteins. [107, 108] Cleavage of the proteolytic TPP2 downstream of the 26S proteasome may promote viral susceptibility as in TRIANGLE disease[109] and may affect the pool of short peptides available for MHC class I presentation. [110]…”

“…[105] Cleavage of ubiquilin-1 between its ubiquitin-associated (UBA) and ubiquitin-like (UBL) domains may disrupt its trafficking ubiquitinated proteins to the proteasome [106] or its targeting of transmembrane proteins. [107,108] Cleavage of the proteolytic TPP2 downstream of the 26S proteasome may promote viral susceptibility as in TRIANGLE disease [109] and may affect the pool of short peptides available for MHC class I presentation. [110] TGF-β is known to be elevated in RA and during alphavirus infection, [111] and its inhibition can reduce joint swelling yet does not reduce viral titer [112] and can even promote CHIKV-mediated cell death in vitro.…”

Previously uncharacterized interactions between the folded and intrinsically disordered domains impart asymmetric effects on UBQLN2 phase separation

“…Both STI1 regions include repeating Asn‐Pro (NP) motifs that are separated by ~10 residues. Notably, a recent computational study predicts each of the STI1‐I and STI1‐II domains of UBQLN1 to consist of multiple helices that make a flexible, helical fold similar to other co‐chaperone proteins 31 . Therefore, it is surprising that STI1‐I, but not STI1‐II would interact with UBL.…”

UBQLN proteins in health and disease with a focus on UBQLN2 in ALS/FTD

“…Besides their roles in facilitating protein degradation, there is growing evidence that UBQLN proteins enhance biosynthesis of membrane proteins, possibly by shielding hydrophobic segments in transmembrane proteins prior to membrane insertion [9,13,[32][33][34][35]. This function has been attributed to its STI1 domains that are known to bind heat shock-related proteins, but the exact mechanism by which they do so remains to be clarified [36][37][38].…”