L. Litovchick et al., THE CARBOXYL-TERMINAL TAIL OF KINASE SPLITTING MEMBRANAL PROTEINASE MEPRIN-BETA IS INVOLVED IN ITS INTRACELLULAR TRAFFICKING, The Journal of biological chemistry, 273(44), 1998, pp. 29043-29051
The kinase splitting membranal proteinase (KSMP), was recently shown t
o be identical with the beta-subunit of meprin. Meprin is a metalloend
oproteinase located in brush border membranes and composed of the two
types of subunits, alpha and beta. Despite their high sequence homolog
y and similar domain organization, meprin subunits are differently pro
cessed during maturation; meprin ct is retained in the endoplasmic ret
iculum (ER), and undergoes a proteolytic removal of the transmembrane
and cytoplasmic domains, prior to its export from this organelle, In c
ontrast, meprin beta retains these domains even after reaching its fin
al destination in the plasma membrane. Using truncated mutants of rat
meprin beta expressed in Cos-7 and human embryonic kidney (HEK) 293 ce
lls, we show here that the cytoplasmic tail is indispensable for its e
xit from the ER, A meprin beta mutant lacking the last 25 amino acids
is shown to be transport-incompetent, although it does not contain any
of the known ER retention signals, Systematic analysis of the rate of
the ER to Golgi transport using a series of mutants with Ala or Pro s
ubstitutions in the tail, suggests that while no specific amino acid r
esidue by itself is imperative for normal intracellular trafficking of
meprin beta, the insertion of a bend at a distinct position in the ta
il (specifically by a Y685P mutation) suffices to retain this protein
in the ER. We propose that the very length of the cytoplasmic tail, as
well as its secondary structure are essential for the ER to Golgi tra
nsport of meprin beta, possibly by allowing an interaction with a carg
o receptor.