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Methods

Identification of novel peptide hormones in the human proteome by hidden Markov model screening

¹ Mouse Biology Unit, EMBL, 00016 Monterotondo, Italy; ² INMM, 00143 Rome, Italy; ³ LIRMM-CNRS, 34392 Montpellier, France; ⁴ Department of Neuroscience, University Tor Vergata Rome, 00133 Rome, Italy; ⁵ European Bioinformatics Institute, EBI-EMBL, CB10 1SD Hinxton, United Kingdom

Peptide hormones are small, processed, and secreted peptides that signal via membrane receptors and play critical roles in normal and pathological physiology. The search for novel peptide hormones has been hampered by their small size, low or restricted expression, and lack of sequence similarity. To overcome these difficulties, we developed a bioinformatics search tool based on the hidden Markov model formalism that uses several peptide hormone sequence features to estimate the likelihood that a protein contains a processed and secreted peptide of this class. Application of this tool to an alignment of mammalian proteomes ranked 90% of known peptide hormones among the top 300 proteins. An analysis of the top scoring hypothetical and poorly annotated human proteins identified two novel candidate peptide hormones. Biochemical analysis of the two candidates, which we called spexin and augurin, showed that both were localized to secretory granules in a transfected pancreatic cell line and were recovered from the cell supernatant. Spexin was expressed in the submucosal layer of the mouse esophagus and stomach, and a predicted peptide from the spexin precursor induced muscle contraction in a rat stomach explant assay. Augurin was specifically expressed in mouse endocrine tissues, including pituitary and adrenal gland, choroid plexus, and the atrio-ventricular node of the heart. Our findings demonstrate the utility of a bioinformatics approach to identify novel biologically active peptides. Peptide hormones and their receptors are important diagnostic and therapeutic targets, and our results suggest that spexin and augurin are novel peptide hormones likely to be involved in physiological homeostasis.

E-mail gross{at}embl.it; fax 39-06-90091272.

[Supplemental material is available online at www.genome.org and at http://bioinfo.embl.it/.]

Article published online before print. Article and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.5755407

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