Structure of the Polycomb Group Protein PCGF1 in Complex with BCOR Reveals Basis for Binding Selectivity of PCGF Homologs

Abstract

Summary Polycomb Group RING finger homologs (PCGF1, 2, 3, 4, 5 and 6) are critical components in the assembly of distinct Polycomb Repression Complex 1 (PRC1) related complexes. Here we identify a protein interaction domain in BCL6 co-repressor, BCOR, which binds the ubiquitin-like RAWUL domain of PCGF1 (NSPC1) and PCGF3 but not of PCGF2 (MEL18) or PCGF4 (BMI1). Because of the selective binding, we have named this domain PCGF Ub-like fold Discriminator (PUFD). The structure of BCOR PUFD bound to PCGF1 reveals 1. that PUFD binds to the same surfaces as observed for a different Polycomb Group RAWUL domain and 2. the ability of PUFD to discriminate among RAWULs stems from the identity of specific residues within these interaction surfaces. These data are the first to show the molecular basis for determining the binding preference for a PCGF homolog, which ultimately helps determine the identity of the larger PRC1-like assembly.

From Flies to Mice: The Emerging Role of Non-Canonical PRC1 Members in Mammalian Development

“…PRC1s are subdivided based on the type PCGFs (PCGF1, 2, 3, 4, 5 and 6) they encompass. Different PCGFs have defined functions, altered binding specificity towards specific accessory subunits [178]. PCGF subunits play critical role in determining the functions of versatile PRC1s.…”

“…The complex is abundant in the nervous system [264], has effective H2A ubiquitin ligase and histone demethylase activity, and targets the CpG islands by KDM2B [265,266] (reviewed in [267]). Resolving the structure of PCGF1-BCOR subcomplex revealed the basis of the binding selectivity of different PCGFs [178].…”

“…BCOR protein is also a member of the BCOR-complex [107], which is named after it. There is a protein-protein interaction motif identified in BCOR called PCGF ubiquitin fold discriminator (PFUD) ( Table 1), which selectively binds the RAWUL domain of PCGF1 and can discriminate between different PCGF RAWUL domains [178]. Wamstad et al found several functions of BCOR both in vivo and in vitro: (1) in bcor neo mutant mice, which exhibit a parent-of-origin effect (with paternally imprinted X-inactivation), it indicates that Bcor is indispensable in extra-embryonic tissue; (2) loss of Bcor results in delayed repression of pluripotency factor Oct3/4 and delayed activation of genes responsible for ectodermal and mesodermal lineage specification during in vitro differentiation of ES cells; and (3) BCOR is also required for formation of primitive erythrocytes [272] and, in Bcor mutants, there is a failure of heart looping [273].…”

Clarifying the Impact of Polycomb Complex Component Disruption in Human Cancers

“…RING1B monoubiquitylates histone H2A on K119, leading to the inhibition of specific transcription targets, including Hox, AP-2a, and Ink4b. LRR, leucine-rich region (7); RAWUL, RING finger-and WD40-associated ubiquitin-like domain (15); PUFD, PCGF Ub-like fold discriminator (15).…”

“…2A, upper lane). However, BCOR mutations tended to accumulate on the C-terminal side of the protein, which contains critical domains that recruit the main components PCGF1/NSPC1 and KDM2B (2,15). Finally, frameshift or nonsense mutations in BCOR have been also reported in 9.5% patients with retinoblastoma (22) and 3.3% patients with medulloblastoma (ref.…”