Exonic splicing code and coordination of divalent metals in proteins

Abstract

Exonic sequences contain both protein-coding and RNA splicing information but the interplay of the protein and splicing code is complex and poorly understood. Here, we have studied traditional and auxiliary splicing codes of human exons that encode residues coordinating two essential divalent metals at the opposite ends of the Irving–Williams series, a universal order of relative stabilities of metal–organic complexes. We show that exons encoding Zn²⁺-coordinating amino acids are supported much less by the auxiliary splicing motifs than exons coordinating Ca²⁺. The handicap of the former is compensated by stronger splice sites and uridine-richer polypyrimidine tracts, except for position –3 relative to 3′ splice junctions. However, both Ca²⁺ and Zn²⁺ exons exhibit close-to-constitutive splicing in multiple tissues, consistent with their critical importance for metalloprotein function and a relatively small fraction of expendable, alternatively spliced exons. These results indicate that constraints imposed by metal coordination spheres on RNA splicing have been efficiently overcome by the plasticity of exon–intron architecture to ensure adequate metalloprotein expression.

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Identifiers

ORCID for Reuben J. Pengelly: orcid.org/0000-0001-7022-645X

ORCID for Martin Chivers: orcid.org/0000-0001-8581-2670

ORCID for Igor Vorechovsky: orcid.org/0000-0002-6740-6502

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