The HERC proteins: functional and evolutionary insights

Abstract

HERC proteins are defined as containing both HECT and RCC1-like domains in their amino acid sequences. Six HERC genes have turned up in the human genome which encode two different sorts of polypeptides: while the small HERC proteins possess little more than the two aforementioned domains, the large ones are giant proteins with a plethora of potentially important regions. It is now almost 10 years since the discovery of the first family member and information is starting to accumulate pointing to a general role for these proteins as ubiquitin ligases involved in membrane-trafficking events. In this review, the available data on these six members are discussed, together with an account of their evolution.

A nonsense variant in HERC1 is associated with intellectual disability, megalencephaly, thick corpus callosum and cerebellar atrophy

“…12 This family consists of two subgroups according to their sizes and domain architecture. The four small proteins (HERC3-6) possess little more than the two above-mentioned domains.…”

“…The two giant HERC1 and HERC2 proteins also contain other functional domains, including two RLDs, a C-terminal HECT, a WD40, a SPRY (spl A and RyR) domain and several other minor motifs. 12 In zebrafish, the HERC1 orthologous gene (LOC569603) is not expressed in the brain suggesting functional divergence between the human and the zebrafish protein and preventing the use of this model to understand how loss of HERC1 protein alter brain development and function (Supplementary Information). By contrast, the murine HERC1 gene is ubiquitously expressed and a variety of mutations have been reported in several members of the HERC families, leading to sterility, growth retardation, retinitis pigmentosa, amyotrophic lateral sclerosis or cancer.…”

“…Indeed, the N-terminus RLD1 domain acts as a GEF guanine nucleotide exchange factor (GEF) for small GTPases and can stimulate guanine nucleotide dissociation from ARF1 and ARF6 GTPases. 12 The ARF proteins are master mediators of membrane trafficking and vesicular transport; 16 misregulation of the ARF proteins causes not only lysosomal-related disorders 17 but also ID as seen in IQSEC2 patients in whom loss of IQSEC2 protein impairs ARF6 activation. 18 It is thus likely that the pathological mechanism underlying the loss of HERC1 involves several pathways, all of which have significant roles in early brain development and function.…”

“…He was born at term after a normal pregnancy, and growth parameters at birth were: weight 4000 g (90th percentile), length 53 cm (90th percentile) and OFC 37 cm (90th percentile). In the first years of life, height (85, 98, 122, 137, 153 at 2, 4, 8, 11 and 14 years of age, respectively) and weight (12,15,23,28, 37 at 2, 4, 8, 11 and 14 years of age, respectively) curves progressively declined at − 1 SD but the OFC curve was above +3 SD, with a final OFC at 66.5 cm at 18 years of age, contrasting with normal parameters for weight (51 kg, − 1 SD) and height (172 cm, M). Skeleton X-rays were normal with no advanced bone age or scoliosis and he had a normal puberty at 13 years of age.…”

Genotype–phenotype associations and human eye color

“…The large HERC2 gene requires 211 kb and 93 exons that codes for a 528 kDa protein made of 4834 residues. 12 OCA2 codes for a major transmembrane protein in the melanosome maturation process: P protein. Similar to membrane-associated transporter protein, it transports melanosomes, but additionally, it controls their pH.…”