Crystal structure of the kringle domain of human receptor tyrosine kinase-like orphan receptor 1 (hROR1)

Abstract

Receptor tyrosine kinase-like orphan receptors (RORs) are monotopic membrane proteins belonging to the receptor tyrosine kinase (RTK) family. RTKs play a role in the control of most basic cellular processes, including cell proliferation, differentiation, migration and metabolism. New emerging roles for RORs in cancer progression have recently been proposed: RORs have been shown to be overexpressed in various malignancies but not in normal tissues, and moreover an abnormal expression level of RORs on the cellular surface is correlated with high levels of cytotoxicity in primary cancer cells. Monoclonal antibodies against the extracellular part of RTKs might be of importance to prevent tumor cell growth: targeting extracellular kringle domain molecules induces the internalization of RORs and decreases cell toxicity. Here, the recombinant production and crystallization of the isolated KRD of ROR1 and its high-resolution X-ray crystal structure in a P3121 crystal form at 1.4 Å resolution are reported. The crystal structure is compared with previously solved three-dimensional structures of kringle domains of human ROR1 and ROR2, their complexes with antibody fragments and structures of other kringle domains from homologous proteins.

Structure and function of the ROR2 cysteine-rich domain in vertebrate noncanonical WNT5A signaling

“…The domains share a small interfacial area of 559 Å 2 , with a reasonable shape complementarity score (0.7) (Lawrence and Colman, 1993). The structure of Kr in the CRD-Kr tandem domain closely resembles that previously described for the isolated human ROR1 and ROR2 Krs (Goydel et al, 2020, Guarino et al, 2022) (Figure 1-figure supplement 2A). Shi et al recently described the structure of the extracellular region of the Drosophila ROR2 homolog Nrk, which consists of a CRD and a Kr domain (Shi et al, 2021).…”

Structure and function of the ROR2 cysteine-rich domain in vertebrate noncanonical WNT5A signaling

“…The domains share a small interfacial area of 559 Å 2 , with a reasonable shape complementarity score (0.7) ( Lawrence and Colman, 1993 ). The structure of Kr in the CRD-Kr tandem domain closely resembles that previously described for the isolated human ROR1 and ROR2 Krs ( Goydel et al, 2020 ; Guarino et al, 2022 ; Figure 1—figure supplement 2A ). Shi et al recently described the structure of the ECD of the Drosophila ROR2 homolog Nrk, which consists of a CRD and a Kr domain ( Shi et al, 2021 ).…”