N-Terminal Proteoforms in Human Disease

The collection of chemically different protein variants, or proteoforms, by far exceeds the number of protein-coding genes in the human genome. Major contributors are alternative splicing and protein modifications. In this review, we focus on those proteoforms that differ at their N termini with a molecular link to disease. We describe the main underlying mechanisms that give rise to such N-terminal proteoforms, these being splicing, initiation of protein translation, and protein modifications. Given their role in several human diseases, it is becoming increasingly clear that several of these N-terminal proteoforms may have potential as therapeutic interventions and/or for diagnosing and prognosing their associated disease.