Epidermal type I transglutaminase (TGM1) is assigned to human chromosome 14.

Human epidermal type I transglutaminase coexists in keratinocytes with another cross-linking enzyme, tissue type II transglutaminase. There are at least five different forms of the enzyme in mammals. Gene mapping studies allowed us to determine whether the different transglutaminases are products of the same gene or separate genes. The gene encoding factor XIII subunit a transglutaminase (F13A1) was previously assigned to human chromosome 6, p24----p25. We demonstrate using somatic cell hybrids that the human epidermal type I transglutaminase gene (gene symbol is designated TGM1) is located on human chromosome 14, providing evidence that at least two human transglutaminases are encoded by separate genes.     

Human type I hair keratin pseudogene ϕ hHaA has functional orthologs in the chimpanzee and gorilla: evidence for recent inactivation of the human gene after the Pan-Homo divergence

In addition to nine functional genes, the human type I hair keratin gene cluster contains a pseudogene, phihHaA (KRTHAP1), which is thought to have been inactivated by a single base-pair substitution that introduced a premature TGA termination codon into exon 4. Large-scale genotyping of human, chimpanzee, and gorilla DNAs revealed the homozygous presence of the phihHaA nonsense mutation in humans of different ethnic backgrounds, but its absence in the functional orthologous chimpanzee (cHaA) and gorilla (gHaA) genes. Expression analyses of the encoded cHaA and gHaA hair keratins served to highlight dramatic differences between the hair keratin phenotypes of contemporary humans and the great apes. The relative numbers of synonymous and non-synonymous substitutions in the phihHaA and cHaA genes, as inferred by using the gHaA gene as an outgroup, suggest that the human hHaA gene was inactivated only recently, viz., less than 240,000 years ago. This implies that the hair keratin phenotype of hominids prior to this date, and after the Pan-Homo divergence some 5.5 million years ago, could have been identical to that of the great apes. In addition, the homozygous presence of the phihHaA exon 4 nonsense mutation in some of the earliest branching lineages among extant human populations lends strong support to the "single African origin" hypothesis of modern humans.     

AMPK β subunits display isoform specific affinities for carbohydrates

AMP-activated protein kinase (AMPK) is a heterotrimer of catalytic (α) and regulatory (β and γ) subunits with at least two isoforms for each subunit. AMPK β1 is widely expressed whilst AMPK β2 is highly expressed in muscle and both β isoforms contain a mid-molecule carbohydrate-binding module (β-CBM). Here we show that β2-CBM has evolved to contain a Thr insertion and increased affinity for glycogen mimetics with a preference for oligosaccharides containing a single α-1,6 branched residue. Deletion of Thr-101 reduces affinity for single α-1,6 branched oligosaccharides by 3-fold, while insertion of this residue into the equivalent position in the β1-CBM sequence increases affinity by 3-fold, confirming the functional importance of this residue.     

The TβR-I pre-helix extension is structurally ordered in the unbound form and its flanking prolines are essential for binding

Transforming growth factor β isoforms (TGF-β) are among the most recently evolved members of a signaling superfamily with more than 30 members. TGF-β play vital roles in regulating cellular growth and differentiation, and they signal through a highly restricted subset of receptors known as TGF-β type I receptor (TβR-I) and TGF-β type II receptor (TβR-II). TGF-β's specificity for TβR-I has been proposed to arise from its pre-helix extension, a five-residue loop that binds in the cleft between TGF-β and TβR-II. The structure and backbone dynamics of the unbound form of the TβR-I extracellular domain were determined using NMR to investigate the extension's role in binding. This showed that the unbound form is highly similar to the bound form in terms of both the β-strand framework that defines the three-finger toxin fold and the extension and its characteristic cis-Ile54-Pro55 peptide bond. The NMR data further showed that the extension and two flanking 3₁₀ helices are rigid on the nanosecond-to-picosecond timescale. The functional significance of several residues within the extension was investigated by binding studies and reporter gene assays in cultured epithelial cells. These demonstrated that the pre-helix extension is essential for binding, with Pro55 and Pro59 each playing a major role. These findings suggest that the pre-helix extension and its flanking prolines evolved to endow the TGF-β signaling complex with its unique specificity, departing from the ancestral promiscuity of the bone morphogenetic protein subfamily, where the binding interface of the type I receptor is highly flexible.