Exon 6 of human JAG1 encodes a conserved structural unit

Alessandro Pintar,Sándor Pongor,Corrado Guarnaccia,Somdutta Dhir

doi:10.1186/1472-6807-9-43

Alessandro Pintar, Sándor Pongor + Show 2 more

Open Access

https://doi.org/10.1186/1472-6807-9-43

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Abstract

BackgroundNotch signaling drives developmental processes in all metazoans. The receptor binding region of the human Notch ligand Jagged-1 is made of a DSL (Delta/Serrate/Lag-2) domain and two atypical epidermal growth factor (EGF) repeats encoded by two exons, exon 5 and 6, which are out of phase with respect to the EGF domain boundaries.ResultsWe determined the 1H-NMR solution structure of the polypeptide encoded by exon 6 of JAG1 and spanning the C-terminal region of EGF1 and the entire EGF2. We show that this single, evolutionary conserved exon defines an autonomous structural unit that, despite the minimal structural context, closely matches the structure of the same region in the entire receptor binding module.ConclusionIn eukaryotic genomes, exon and domain boundaries usually coincide. We report a case study where this assertion does not hold, and show that the autonomously folding, structural unit is delimited by exon boundaries, rather than by predicted domain boundaries.

Highlights

Notch signaling drives developmental processes in all metazoans
We report here the solution structure of J1ex6 determined by 1H-NMR spectroscopy and demonstrate that exon 6 defines an epidermal growth factor (EGF)-like structural unit with an additional disulfide-linked loop in the N-terminal overhang
The overall correspondence is maintained, with exons 5 and 6 encoding EGF1 and 2, but exon and domain boundaries are clearly out of phase, with exon 5 encoding a truncated EGF with only four half-cystines and exon 6 encoding the C-terminal half of EGF1 and the entire EGF2

Summary

Introduction

The receptor binding region of the human Notch ligand Jagged-1 is made of a DSL (Delta/Serrate/Lag-2) domain and two atypical epidermal growth factor (EGF) repeats encoded by two exons, exon 5 and 6, which are out of phase with respect to the EGF domain boundaries. Notch signaling controls cell lineage decisions in tissues derived from all three primary germ lines: endoderm, mesoderm, and ectoderm playing an essential role in organogenesis [1,2,3] Both receptors and ligands are membrane-bound proteins, which normally restricts signaling to adjacent cells. Jagged-1, one of the five Notch ligands identified in man, is a single pass type I membrane protein with a large extracellular region made of a poorly characterized N-terminal region, a DSL (Delta/Serrate/Lag-2) domain, a series of 16 epidermal growth factor (EGF) tandem repeats, and a cysteine-rich juxtamembrane region (Figure 1). We prepared a longer peptide encompassing the C-terminal part of EGF1 and the entire EGF2 (Figure 1)

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