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Biochemical Analysis of the Polycystin-1 Complexity Generated by Proteolytic Cleavage at the G Protein-Coupled Receptor Proteolysis Site
Published in Jinghua Hu, Yong Yu, Polycystic Kidney Disease, 2019
Rebecca Walker, Hangxue Xu, Qiong Huang, Feng Qian
Situated at the base of the ectodomain is the 50-aa GPS motif16,17,50 (Figure 1.1a). The GPS motif was first identified in a neuronal GPCR, CIRL/latrophilin,51 and has recently been recognized as a part of the larger GPCR autoproteolysis-inducing (GAIN) domain that is also present in PC1.19 The GAIN domain is a defining feature of the adhesion GPCRs (aGPCRs),19,52 the second largest subgroup of GPCRs in the human genome.53,54 The GPS/GAIN domain is the primary site for PC1 processing, allowing a much greater complexity of the PC1 pool to be generated and allowing for modulation of PC1 function. PC1 is cleaved between leucine (L) and threonine (T) at the highly conserved HL↓T tripeptide sequence within the GPS10 (see Figure 1.1a), resulting in two cleavage products, PC1NTF and PC1CTF. The reaction takes place in the ER shortly after PC1 synthesis. GPS cleavage of PC1 occurs via a cis-autoproteolytic mechanism10 (Figure 1.1b). This mechanism was found in an aGPCR, EMR2,56 and is similar to those found in other autoproteolytic proteins such as the Ntn hydrolases57,58 and hedgehog proteins.59 Cis-autoproteolysis is a self-catalyzed chemical rearrangement based on the ability of the nucleophilic Thr residue of the tripeptide HL↓T to initiate a proximal N–O acyl rearrangement. This converts the peptide (amide) bond to a more reactive ester intermediate.60 A second nucleophile, such as a water molecule, attacks the ester bond, leading to the irreversible cleavage of the scissile bond.10
Retrospective study demonstrating therapy time impact on inpatient rehabilitation functional gains
Published in Disability and Rehabilitation, 2022
Pamela S. Roberts, Debra Ouellette, Nuvia Solis, Robert Walters, Kathy Chambers, David Brown, Margaret A. DiVita
Pearson’s correlation coefficients between therapy hours per day (by discipline) and all continuous variables are displayed in Table 2; these variables include functional variables (FIM), age as a continuous variable, rehabilitation length of stay, and onset days (number of days from onset of impairment to admission to the IRF). For PT hours per day, while the p values for all correlations were highly significant (at the 0.01 level), all correlation coefficients were relatively low. The highest was 0.158 for the locomotion domain gains. However, these are still weak correlation coefficients [34]. For OT hours per day, the p values for most of the variables were highly significant, p < 0.001; however, the correlation coefficients were mainly low except for self-care domain gains (r = 0.660). For SLP hours per day, similarly to OT and PT, there are many highly significant p values (<0.01); similarly, most were weak coefficients except for the cognitive FIM gain domain (r = 0.233) and the communication FIM gain domain (r = 0.259). These results are expected, as SLP therapists work mostly with these domains.
Opportunities and challenges for drug discovery in modulating Adhesion G protein-coupled receptor (GPCR) functions
Published in Expert Opinion on Drug Discovery, 2020
Andrey D. Bondarev, Misty M. Attwood, Jörgen Jonsson, Vladimir N. Chubarev, Vadim V. Tarasov, Helgi B. Schiöth
The aGPCR family consists of the following members: ADGRL 1–4 (Latrophillin subfamily/subfamily L), ADGRE 1–5 (EGF–7TM subfamily/subfamily E), ADGRA 1–3 (subfamily A), ADGRC 1–3 (CELSR subfamily/subfamily C), ADGRD 1 and 2 (subfamily D), ADGRF 1–5 (subfamily F), ADGRB 1–3 (BAI subfamily/subfamily B), ADGRG 1–7 (subfamily G) and ADGRV 1 (subfamily V). The receptors’ structures are schematically depicted in Figure 1. Apart from the long and structurally diverse N-terminal domains, the other unique features of aGPCRs are the presence of the GPCR autoproteolysis–inducing (GAIN) domain [12] and the GPCR proteolysis site (GPS) motif [13]. The GPS is found within the GAIN domain and both are responsible for signaling activation through a tethered peptide agonist (also referred to as the Stachel sequence) [14]. The aGPCRs architecture layout varies depending on the receptors’ ability to undergo GPS-mediated autoproteolysis (Figure 2) [15,16]. All aGPCRs are characterized by the three-partite topology-based structure compartmentation, which includes extracellular (ECD) and intracellular domains (ICD) separated by 7TM domains (Figure 2(a)). Receptors with cleavable GAIN domains are capable of undergoing autoproteolysis and can additionally produce the two-partite cleavage-based structure layout, containing N-terminal (NTF) and C-terminal (CTF) fragments (Figure 2(b)).
A review of antibody-based therapeutics targeting G protein-coupled receptors: an update
Published in Expert Opinion on Biological Therapy, 2020
The GPCR superfamily consists of several sub-families: Class A (rhodopsin family) is the largest GPCR family by far, includes the chemokine receptors and comprises the largest group of targets for existing drugs. The main biological role of the chemokine receptors is to mediate leukocyte trafficking to sites of inflammation, but additional roles have been identified in the areas of embryonic development, viral infection and immune cell proliferation, activation and death. Several Class A GPCRs have very short N-terminal domains; however, chemokine and glycoprotein hormone receptors have large N-terminal domains [7]. Class B GPCRs (secretin family) are activated by peptide hormones and also exhibit large N-terminal domains. Noted for their metabolic role, Class B GPCRs coordinate homeostatic regulation, neural and endocrinal activity. Class C GPCRs have an even larger bi-lobed N terminal that is distal to the TMD and this is known as the ‘Venus flytrap.’ Another distinguishing feature of this GPCR family is the ability to form constitutive dimers with unique activation modes. Class C GPCRs play a major role in the CNS and calcium homeostasis and include the metabotropic glutamate receptors, GABAB receptors and calcium-sensing receptors. Adhesion GPCRs (aGPCRs) share structural similarities with Family B GPCRs possessing a very large multi-domain N-terminal domain. This large extracellular domain (ECD) is thought to interact with extracellular matrix proteins and other cell surface markers. A unique feature of aGPCRs is the autocatalytic cleavage of the ECD from the TMD at a unique highly conserved site proximal to the TMD known as the GPCR autoproteolysis-inducing domain, or GAIN domain, thereby generating a ‘tethered’ ligand which activates the aGPCR [8]. Other domains within the complex N terminal of aGPCRs are involved in cell adhesion, as well as cell:cell communications, and thought to play an important role in embryonic development, with some thought to function as mechanosensors [8]. The last major class of GPCRs is the Frizzled (FZD) family, which also includes Smoothened (SMO) for which there are two approved small-molecule inhibitors for the treatment of basal cell carcinoma. FZD family members possess an extracellular domain of ~120 amino acids known as the fz domain. The fz domain is also known as the CRD (cysteine-rich domain) as this contains 10 cysteine residues that are highly conserved. FZD GPCRs are activated by cysteine-rich lipoglycoproteins known as Wnt proteins and signal via the Wnt pathway, whereas SMO signals via the Hedgehog pathway. This GPCR family is involved in ontogeny and tissue homeostasis. Finally, although ~130 other GPCRs have been identified from their sequence identity, the corresponding ligand is still unknown; these are known as orphan GPCRs. Given their role in many disease indications, this represents a significant valuable source of targets yet to be interrogated extensively.