Understanding cadherin EGF LAG seven-pass G-type receptors

Abstract

The cadherin epidermal growth factor (EGF) laminin G (LAG) seven-pass G-type receptors (CELSRs) are a special subgroup of adhesion G protein-coupled receptors, which are pivotal regulators of many biologic processes such as neuronal/endocrine cell differentiation, vessel valve formation, and the control of planar cell polarity during embryonic development. All three members of the CELSR family (CELSR1-3) have large ecto-domains that form homophilic interactions and encompass more than 2000 amino acids. Mutations in the ecto-domain or other gene locations of CELSRs are associated with neural tube defects and other diseases in humans. Celsr knockout (KO) animals have many developmental defects. Therefore, specific agonists or antagonists of CELSR members may have therapeutic potential. Although significant progress has been made regarding the functions and biochemical properties of CELSRs, our knowledge of these receptors is still lacking, especially considering that they are broadly distributed but have few characterized functions in a limited number of tissues. The dynamic activation and inactivation of CELSRs and the presence of endogenous ligands beyond homophilic interactions remain elusive, as do the regulatory mechanisms and downstream signaling of these receptors. Given this motivation, future studies with more advanced cell biology or biochemical tools, such as conditional KO mice, may provide further insights into the mechanisms underlying CELSR function, laying the foundation for the design of new CELSR-targeted therapeutic reagents. The cadherin EGF LAG seven-pass G-type receptors (CELSRs) are a special subgroup of adhesion G protein-coupled receptors (GPCRs), which have large ecto-domains that form homophilic interactions and encompass more than 2000 amino acids. Recent studies have revealed that CELSRs are pivotal regulators of many biological processes, such as neuronal/endocrine cell differentiation, vessel valve formation and the control of planar cell polarity during embryonic development.

Keywords: CELSR; G protein-coupled receptor; adhesion; development; planar cell polarity.

Figure 1. Domain architecture of the CELSR protein

(A/B) Snake-like domain architecture of CELSR1-3 proteins. Domains are indicated by shaded boxes with different colors, with the exception of trans-membrane regions, which are highlighted by brown bars with helices; purple, GAIN domain; red, HormR domain; green, EGF-Lam domain; orange, EGF-CA domain; magenta, LamG domain; and blue, cadherin repeat.

Figure 2. Sequence alignments of the GPS and transmembrane region of the CELSR1-3

(A) Sequence alignment of the GPS for CELSR1-3 proteins and several other adhesion GPCRs. (B) Sequence alignment of the transmembrane regions of the CELSR proteins from humans, mice and Drosophila.

Figure 3. Schematics for the signaling cascade downstream of CELSR1

The signaling cascade downstream of CELSR1 during the regulation of neural tube closure.

Figure 4. Novel CELSR1 mutations in patients with neural tube defects (NTDs)

A schematic representation of the predicted protein structure of CELSR1 with structural modules (left) and the approximate positions of different NTDs mutations (right) indicated by arrows. Abbreviations: aa, amino acids; EGF, epidermal growth factor; GAIN, GPCR Autoproteolysis Inducing (GAIN) domain. GPS, G protein-coupled receptor proteolytic site; and TM, transmembrane.