PICALM (clathrin assembly lymphoid myeloid leukemia gene)

11q14.2

24 transcripts

PICALM codes for a 652-aa protein, and shorter isoforms. It is an endocytosis adaptor, in the initial stages of coated pit invagination together with clathrin, AP2 (adaptor related protein complex subunits) and PtdIns(4,5)P2 (phosphatidylinositol-4,5- bisphosphate) containing membranes. PICALM interacts with CLTC (clathrin heavy chain) promoting assembly of clathrin triskelia into clathrin cages. Clathrin is the major binding partner of PICALM (Archangelo et al., 2006). PICALM is required for erythroid maturation and transferrin internalization.
PICALM domains: PICALM contains an AP180 N-terminal homology (ANTH) domain (or ENTH domain for epsin NH2-terminal domain)) (note: "AP180" is SNAP91, and epsin is EPN1, EPN2 or EPN3) and an assembly domain (AD). ANTH: amino acids (aa) 1-289; AD: aa 290-652.
ANTH: The ANTH domain is folded; it binds phosphatidylinositol-4,5- bisphosphate (PtdIns(4,5)P2) via a lysine-rich motif, and vesicle associated membrane proteins (VAMPs). There are nine alpha helices forming a solenoid (aa 20-30, 40-50, 56-67, 71-90, 91-100, 115-142, 160-180, 191-222, 225-258). In addition, there are PtdIns(4,5)P2-binding residues at aa 28, 38, 40, 41 (K, K, K, H).
AD: The AD has two subdomains: a central clathrin and adaptor protein binding (CLAP) domain and the remainder is an unnamed domain (ADΔCLAP). CLAP domain: aa 290-525, with CLAP motifs: DIF, DLL, DPF (see below), and FESVF: aa 488-493. Unnamed domain (ADΔCLAP): aa 526-652. ADΔCLAP is basic. The assembly domain (AD) has a role of clathrin and AP2 binding.
Other domains: transcriptional activation domain (TAD) (aa 408-572). PICALM is O-GlcNAc modified at aa 454 (S). Nuclear export signal (NES) LANLVGNLGI: aa 544-553. The NES consensus sequence is ΦX1-3ΦX2-3ΦXΦ, where Φ is most often leucine. The NES is the factor which contributes to PICALM/MLLT10 mediated leukemogenesis.
Protein interaction domains: PICALM binds directly to various vesicle associated membrane proteins: VAMP2 , VAMP3, VAMP4, VAMP7 and VAMP8. PIMREG (FAM64) interaction domain: aa 221-294; FHL2 interaction domain: aa 294-335; proteins with an EPS15 homology domain interaction domain: NPF (Asp-Pro-Phe) motif (aa 437-439). Clathrin binding motifs (CBM): Binding of clathrin heavy chain (CLTC) involves primarily aa 413-652, however, the entire AD is required for efficient clathrin binding. PICALM has one DLL (Asp-Leu-Leu) motif (aa 392-394); one DIF (Asp-Ile-Phe) motif (aa 375-377) which could bind clathrin, but also AP2A1 (AP2 alpha subunit); and one DPF (Asp-Pro-Phe) sequence (aa 420-422), which can also bind AP2A1. Other clathrin binding sequences involve L/I (Leu/Ile) in aa 540-553 and aa 649-652 (Tebar et al., 1999; Ford et al., 2001; Archangelo et al., 2006; Pašaliç et al., 2011; Moshkanbaryans et al., 2014; Moshkanbaryans et al., 2016).

KMT2A (myeloid/lymphoid or mixed lineage leukemia)

11q23.3

37 exons, spanning about 120 kb; 13-15 mRNA

3969 amino acids, 431 kDa; Transcriptional regulatory factor. MLL is known to be associated with more than 30 proteins, including the core components of the SWI/SNF chromatin remodeling complex and the transcription complex TFIID. MLL binds promotors of HOX genes through acetylation and methylation of histones. MLL is a major regulator of hematopoesis and embryonic development, through regulation of HOX genes expression regulation (HOXA9 in particular).