A class of secreted mammalian peptides with potential to expand cell-cell communication
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Abstract
Peptide hormones and neuropeptides are signaling molecules that control diverse aspects of mammalian homeostasis and physiology. Here we provide evidence for the endogenous presence of a sequence diverse class of blood-borne peptides that we call “capped peptides.” Capped peptides are fragments of secreted proteins and defined by the presence of two post-translational modifications – N-terminal pyroglutamylation and C-terminal amidation – which function as chemical “caps” of the intervening sequence. Capped peptides share many regulatory characteristics in common with that of other signaling peptides, including dynamic physiologic regulation. One capped peptide, CAP-TAC1, is a tachykinin neuropeptide-like molecule and a nanomolar agonist of mammalian tachykinin receptors. A second capped peptide, CAP-GDF15, is a 12-mer peptide cleaved from the prepropeptide region of full-length GDF15 that, like the canonical GDF15 hormone, also reduces food intake and body weight. Capped peptides are a potentially large class of signaling molecules with potential to broadly regulate cell-cell communication in mammalian physiology.
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cognate receptors
Curious how specific these cognate receptors are with peptides?
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we performed a multiple sequence alignment to globally understand the sequence relationship and homology across all capped peptide sequences from both mice and humans.
Would you be interested in extending this analysis beyond human and mice? Would be really fascinating to understand the evolutionary history of this across more species and lineages. Maybe this could even help shed new insights on to overarching biological functions these enable?
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Our detection of CAP-FGF5 and CAP-GDNF suggests that FGF5 and GDNF might also exhibit endocrine functions via cleavage fragments generated the pre-proprecursor sequences.
This is wild and so fun to think about. Especially since it's the tip of an iceberg of dark matter functions!
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preproprecursor
is this a typo or do you mean pre-proprecursor?
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circulating concentrations in the range of ∼0.1-100 nM
Curious if this is higher or lower than you expected? And what the implications of these levels may be with regard to their function or capping?
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coincident N-pyroglutamyl and C-amidation modifications,
Love this angle. Are there classes of peptides with only one of these? And how do they compare numbers-wise? And what might be unique about having the coincident N/C mods?
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