The BEACH Is Hot: A LYST of Emerging Roles for BEACH‐Domain Containing Proteins in Human Disease

Abstract

BEACH (named after ‘Beige and Chediak-Higashi’) is a conserved ~280 residue domain, present in nine human BEACH domain containing proteins (BDCPs). Most BDCPs are large, containing a PH-like domain for membrane association preceding their BEACH domain, and containing WD40 and other domains for ligand binding. Recent studies found that mutations in individual BDCPs cause several human diseases. BDCP alterations affect lysosome size (LYST and NSMAF), apoptosis (NSMAF), autophagy (LYST, WDFY3, LRBA), granule size (LYST, NBEAL2, NBEA), or synapse formation (NBEA). However, the roles of each BDCP in these membrane events remain controversial. After reviewing studies on individual BDCPs, we propose a unifying hypothesis that BDCPs act as scaffolding proteins that facilitate membrane events, including both fission and fusion, determined by their binding partners. BDCPs may also bind each other, enabling fusion or fission of vesicles that are not necessarily of the same type. Such mechanisms explain why different BDCPs may have roles in autophagy; each BDCP is specific for the cell type or the cargo, but not necessarily specific for attaching to the autophagosome. Further elucidation of these mechanisms, preferably carrying out the same experiment on multiple BDCPs, and possibly using patients’ cells, may identify potential targets for therapy.

Should any genetic defect affecting α‐granules in platelets be classified as gray platelet syndrome?

“…Notwithstanding the phenotypic variability, a large number of GPS families, all with autosomal recessive inheritance, genotyped with biallelic mutations in NBEAL2 [10][11][12][13]. Significantly, neurobeachin-like 2 (NBEAL2) is predicted to be scaffolding protein that intervenes in vesicle trafficking, it contains a Beige and ChediakHigashi (BEACH) domain also seen in lysosomal trafficking regulator (LYST) mutated in the Chediak-Higashi syndrome and associated with abnormal lysosomes and dense granules [14]. Strikingly, in GPS missense, nonsense, and frameshift mutations as well as altered spicing variants are found all along the gene and all basically caused the same phenotype showing that an absent or functionally defective protein interferes severely in a-granule biogenesis (Fig.…”

Novel protein Callipygian defines the back of migrating cells

“…Although CynA lacks sequence homology to proteins in higher eukaryotes, it may have functional homologs because several mammalian proteins share a similar domain composition. For example, the Rho GEF ARHGEF10 and several BEACH domain family proteins, including neurobeachin (NBEA), lipopolysaccharide-responsive, beige-like anchor protein (LRBA), lysosomal trafficking regulator (LYST), and neutral sphingomyelinase activation-associated factor (NSMAF), contain both WD40 and PH domains (33).…”

α-Granules at the BEACH

“…Nbeal2 is a member of a family of proteins known as BEACH-domain-containing proteins (BDCP). 8 The BEACH domain gained its name because the charter family member-LYST/CHS1 (lysosomal trafficking regulatory/Chediak-Higashi syndrome 1 protein), defective in the beige mouse and in human Chediak-Higashi syndrome (MIM 214500)-contained this unusual ;300 amino acid domain. 9 This domain has a unique peptide-backbone fold, in that its core does not assume regular secondary structures.…”

“…10 The highly conserved BEACH domain has now been identified in 9 human proteins and in numerous species. 8 Most members of this family of generally high molecular weight proteins contain Further studies will be required to fully understand Nbeal2's role in megakaryocyte differentiation. Mouse models have been invaluable tools in understanding human disease.…”