Serine (Ser, S)
Serine is a small, polar amino acid with a hydroxymethyl side chain. It is a major site of phosphorylation and O-glycosylation and is common in flexible linkers and turns.
Structure and properties
Serine has a short side chain ending in a primary hydroxyl group. The hydroxyl is polar and uncharged, can donate and accept hydrogen bonds, and makes serine hydrophilic and common on protein surfaces. Its small size and hydrogen-bonding ability let it cap helices and sit in turns. The hydroxyl is a weak nucleophile on its own, but in the catalytic triads of serine proteases it is activated to attack peptide bonds. In cells, serine hydroxyls are major sites of phosphorylation by kinases and of O-linked glycosylation.
Role in peptides
Serine is widely used in flexible Gly-Ser linkers and to improve solubility. It appears in Kisspeptin-10, DSIP and LL-37, and native GLP-1 contains serine in its N-terminal region, retained in semaglutide. Thymosin α1 begins with an N-acetylated serine. Ghrelin carries an octanoyl group esterified to a serine side chain, which is required for its receptor activity. Serine is also part of the N-glycosylation sequon Asn-X-Ser and speeds deamidation of a preceding asparagine.
Stability and analysis
Serine is fairly stable. Under strong acid, as in cleavage, an N-to-O acyl shift can move the backbone onto the serine hydroxyl, a reversible change that alters HPLC behaviour. Under basic conditions, serine and especially phosphoserine can undergo beta-elimination. In synthesis, unprotected hydroxyls can be acylated, so tert-butyl protection is standard. Serine after asparagine accelerates deamidation, so Asn-Ser motifs deserve attention in stability data.
In PeptideWiki compounds
Compounds whose sequence contains serine, with the number of occurrences.
- IGF-1 LR3 (7)
- Exenatide (5)
- Calcitonin (salmon) (4)
- Tesamorelin (4)
- Thymosin β4 (4)
- CJC-1295 (3)
- Pramlintide (3)
- Sermorelin (3)
- Teriparatide (3)
- Thymosin α1 (3)
- AOD-9604 (2)
- ARA-290 (cibinetide) (2)
- Abaloparatide (2)
- Afamelanotide (2)
- Humanin (2)
- LL-37 (2)
- VIP (vasoactive intestinal peptide) (2)
- DSIP (1)
- Gonadorelin (1)
- Kisspeptin-10 (1)
- Matrixyl (palmitoyl pentapeptide-4) (1)
- Triptorelin (1)
Frequently asked questions
Why is serine phosphorylated so often?
Serine's hydroxyl is accessible and sits on a flexible side chain, so kinases can reach it in many sequence contexts. Adding a phosphate introduces a strong negative charge that can switch protein binding, activity or location. Serine, threonine and tyrosine are the main phosphorylation sites in eukaryotic cells, with serine the most common. Synthetic phosphopeptides are widely used as kinase substrates and antibody antigens.
What is an N-to-O acyl shift?
In strong acid, the backbone carbonyl before a serine or threonine can migrate from the nitrogen to the side-chain oxygen, forming an ester in place of the amide. The change is reversible on raising pH but can appear as an extra peak during analysis if samples sit in acid. The same chemistry is exploited deliberately in O-acyl isopeptides, which are used to improve solubility during synthesis of aggregation-prone sequences.
Cite this page