Table I. Methods for enriching protein N and C termini.

Methoda	Advantages/disadvantages	Quantitation	Reference(s)
Selective enzymatic biotinylation of N termini	(+) Positive selection of unmodified N termini	iTRAQ, SILAC, label-free selected reaction monitoring	(32, 33, 61, 86, 87)
	(+) Does not require chemical modification
	(−) Requires expensive patent protected enzyme
	(−) Requires large amounts of sample
N-CLAP	(+) Positive selection of unmodified N termini	None to date	(34)
	(−) Enriched peptides are shortened by one residue
	(−) Not compatible with chemical stable-isotope labeling
COFRADIC	(+) Negative selection of N and C termini	12C4 and 13C4 butyric acid, NHS-13C2D3, SILAC, trypsin-catalyzed 18O exchange	(35, 36, 55, 88–90)
	(−) Extensive fractionation enhances sample loss
	(−) >50 fractions/sample, making it very instrument intensive
	(−) Loss of His- and Arg-containing peptides during strong cation exchange chromatography
TAILS	(+) Negative selection of modified and unmodified N-termini	Stable-isotope dimethyl labeling, iTRAQ	(37, 79, 80, 91, 92)
	(+) Very low nonspecific binding to polymer
	(−) Requires commercially available hyperbranched polyglycerol aldehyde polymer
PTAG	(+) Negative selection of modified and unmodified N termini	None to date	(40)
	(−) Loss of phosphorylated N-terminal peptides
	(−) Losses due to nonspecific binding to TiO2 material
Enrichment of modified N termini by selective α-amine biotinylation	(+) Negative selection of modified N termini	None to date	(41, 42)
	(−) No retention of unmodified N termini
	(−) Loss of His-containing peptides
C-TAILS	(+) Negative selection of modified and unmodified C termini	Stable-isotope dimethyl labeling	(54)
	(+) Chemical tag identifies unmodified C termini
	(−) Difficult to achieve complete labeling of carboxyl groups

^a Published name or description of enrichment method.

SILAC, stable isotope labeling by amino acids in cell culture.