Secernin-3 (SCRN3)

Secernin-3 (SCRN3) is a 424-amino acid protein encoded by the SCRN3 gene located on chromosome 2q31.1[2]. It belongs to the peptidase C69 family and the secernin subfamily, with a molecular weight of approximately 48.4 kDa[2]. SCRN3 is predicted to have cysteine-type exopeptidase activity and dipeptidase activity[2]. The protein is ubiquitously expressed throughout the brain and 25 other tissues, with particularly high expression in brain, thyroid, heart, and prostate[2]. A unique feature of SCRN3 is its N-terminal glyoxylyl (Glox) group, which represents the first naturally occurring N-terminal glyoxylyl electrophile identified in mammalian proteins[1][2]. This Glox group is formed through post-translational modification of a cysteine residue and serves as a cofactor that can be covalently targeted by hydrazine-containing compounds like phenelzine[1]. Recent research has revealed that SCRN3 plays a role in thermal nociception, as male knockout mice exhibit impaired thermal nociceptive sensitivity[1]. The protein's expression is regulated by pro-inflammatory pathways, particularly through lipopolysaccharide (LPS) stimulation via Toll-like receptor 4 (TLR4) signaling[1]. This inflammatory regulation, combined with its role in pain processing, suggests SCRN3 may be involved in the transition from acute to chronic pain states[1]. The discovery of SCRN3 as a target emerged from activity-based protein profiling studies using phenelzine-based chemical probes, revealing it as an unexpected off-target of this antidepressant medication in brain tissue[1]. While SCRN3 knockout mice are viable and fertile without obvious developmental defects, the selective thermal nociception phenotype in males indicates sex-specific functional roles[1]. The protein's conservation across species from invertebrates to mammals, combined with its druggable Glox cofactor, positions SCRN3 as a potential therapeutic target for pain management and inflammatory conditions[1][2].

Other names

SES3FLJ23142secernin 3

Covalent inhibition via N-terminal glyoxylyl group