Structure of human BCCIP and implications for binding and modification of partner proteins

Abstract

BCCIP was isolated based on its interactions with tumor suppressors BRCA2 and p21. Knockdown or knockout of BCCIP causes embryonic lethality in mice. BCCIP deficient cells exhibit impaired cell proliferation and chromosome instability. BCCIP also plays a key role in biogenesis of ribosome 60S subunits. BCCIP is conserved from yeast to humans, but it has no discernible sequence similarity to proteins of known structures. Here we report two crystal structures of an N‐terminal truncated human BCCIPβ, consisting of residues 61–314. Structurally BCCIP is similar to GCN5‐related acetyltransferases (GNATs) but contains different sequence motifs. Moreover, both acetyl‐CoA and substrate‐binding grooves are altered in BCCIP. A large 19‐residue flap over the putative CoA binding site adopts either an open or closed conformation in BCCIP. The substrate binding groove is significantly reduced in size and is positively charged despite the acidic isoelectric point of BCCIP. BCCIP has potential binding sites for partner proteins and may have enzymatic activity.

Inhibition of FAM46/TENT5 activity by BCCIPα adopting a unique fold

“…S2A). Strikingly, the structure showed that BCCIPα adopts a structural fold that is completely different from the structure of BCCIPβ published previously (see details below) ( 34 , 35 ). Analyses of this structure allowed us to design a new construct, BCCIPα-ΔL, containing a larger deletion (residues 231 to 280) of a long disordered loop (fig.…”

“…The previously published structures of BCCIPβ from human and yeast both exhibit a fold similar to GCN-5-related acetyltransferases, characterized by a splayed seven-stranded β sheet that is surrounded by several α helices on each side (Fig. 4A) (34,35). BCCIPβ is, however, unlikely an acetyltransferase because it lacks the catalytic residues conserved in those enzymes (34,35).…”

“…4A ) ( 34 , 35 ). BCCIPβ is, however, unlikely an acetyltransferase because it lacks the catalytic residues conserved in those enzymes ( 34 , 35 ). BCCIPα also contains a central β sheet, but the order and directions of the β strands are entirely different from those in BCCIPβ ( Fig.…”

“…Notably, models of BCCIPα generated by AlphaFold without using structural templates and ESMFold that uses language model-based prediction closely resemble the structure of BCCIPβ, rather than that of BCCIPα solved here (fig. S4) (34)(35)(36)(37)(38). Furthermore, A DALI search of the protein structural database suggested that the fold of BCCIPα is unique, as the search failed to find any protein with substantial similarity to BCCIPα.…”