The crystal structure of human Rogdi provides insight into the causes of Kohlschutter-Tönz Syndrome

Abstract

Kohlschutter-Tönz syndrome (KTS) is a rare autosomal-recessive disorder of childhood onset characterized by global developmental delay, spasticity, epilepsy, and amelogenesis imperfecta. Rogdi, an essential protein, is highly conserved across metazoans, and mutations in Rogdi are linked to KTS. However, how certain mutations in Rogdi abolish its physiological functions and cause KTS is not known. In this study, we determined the crystal structure of human Rogdi protein at atomic resolution. Rogdi forms a novel elongated curved structure comprising the α domain, a leucine-zipper-like four-helix bundle, and a characteristic β-sheet domain. Within the α domain, the N-terminal H1 helix (residues 19–45) pairs with the C-terminal H6 helix (residues 252–287) in an antiparallel manner, indicating that the integrity of the four-helix bundle requires both N- and C-terminal residues. The crystal structure, in conjunction with biochemical data, indicates that the α domain might undergo a conformational change and provide a structural platform for protein–protein interactions. Disruption of the four-helix bundle by mutation results in significant destabilization of the structure. This study provides structural insights into how certain mutations in Rogdi affect its structure and cause KTS, which has important implications for the development of pharmaceutical agents against this debilitating neurological disease.

Kohlschütter-Tönz Syndrome With a Novel ROGD1 Variant in 3 Individuals: A Rare Clinical Entity

“…19 Although the function of the ROGDI gene is not fully clarified, it has been suggested that it is responsible for efficient signals for presynaptic targeting. [19][20][21] Riemann et al 19 also concluded that Rogdi could affect neuronal migration, axonal pathfinding, or synapse formation in a subset of neurons early during development, causing a neurodevelopmental phenotype. Although it has been reported that Rogdi is expressed in the stage of odontogenesis in mouse embryos, 22 the precise role in dental phenotypes of Kohlschütter-Tönz syndrome has not yet been fully understood.…”

Kohlschütter–Tönz syndrome: Case report with novel feature and detailed review of features associated with ROGDI variants

“…The crystal structure reveals that ROGDI protein contains two distinct domains α and β. The α domain consists of four helices that form a left-handed four-helix bundle, and the β domain comprises two β-sheets each containing four antiparallel β-strands and flanked by two short α-helices (Lee et al, 2017). Typical leucine zipper proteins, such as transcription factors, dimerize to bind to DNA.…”

Rogdi Defines GABAergic Control of a Wake-promoting Dopaminergic Pathway to Sustain Sleep in Drosophila

“…3 ) although the exclusive nuclear localization might not be a prerequisite for transcriptional activities. We recently reported the crystal structure of human ROGDI protein 62 and showed that, unlike other bZIP transcription factors, human ROGDI protein exists as a monomer containing two structurally distinguishable domains (designated as α and β domains, respectively) (Supplementary Fig. 2a ).…”