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.

Figure 1. Amino acid alignment of the BEACH domains of the human BDCPs

Completely conserved amino acids are highlighted in cyan, semi-conserved in grey, and non-conserved are given in lower case letters with no highlight. Amino acid position numbers are given on the right and represent the last amino acid on each line. These numbers are based on translation of the longest mRNA transcript of each BDCP (shown in Table 1). Note the 8–15 amino acid insertion in LYST compared to other BDCPs. Red boxes represent missense mutations that have been identified in the BEACH domain. Arrows and numbers call attention to the columns with the red boxes. 1 = LRBA - p.R2224W (UDP data); 2 = NBEAL2 - p.P2100L (10); 3 = NBEAL1 - p.R2077Q (UDP data); 4 = NBEAL2 - p.H2263Y (9); 5 = NBEAL2 - p.S2269L (10); 6 = WDR81 - p.G538R (UDP data); 7 = WDR81 - p.A546G (UDP data); and 8 = LYST - p.N3376S (16).

Figure 2. Schematic diagram displaying recognized protein domains in human BDCPs

The BEACH domain is aligned for all nine proteins and the drawing is to scale, where the scale bar represents 250 amino acids. Note the similarity in number and positions of the WD40 repeat domains following, and the PH domains preceding the BEACH domain in 7 out of the 9 proteins. Other recognized domains include ConA-like lectin, DUF1088, ARM, FYVE and GRAM domains.

Figure 3. Schematic abstract diagram showing the proposed scaffold function of BDCPs

The example shown here is for LYST and WDFY3 because they are predicted to interact in silico and because these are the only two BDCPs for which binding partners were investigated. However, this hypothesis can be translated hetero- and homo-typic combinations of other BDCPs. (1) BDCPs first recognize their specific membranes through their PH-like and BEACH domain segment, possibly with the aid of other domains more specific to some BDCPs. (2) The BDCPs then interact with each other forming a scaffold holding vesicles or membranes in place for further membrane events. (3) The BDCP scaffold acts as a platform for other proteins and lipids to be recruited and interact with the BDCPs and/or with the vesicular membranes. These binding partners required for subsequent membrane events are largely undiscovered. In the case of WDFY3 and the autophagosome membrane, p62 (SQSTM1) is a critical interacting protein, whose interaction with WDFY3 facilitates further interactions with ATG proteins with defined roles in autophagy (references , –63).