Biomedical Engineering Reference
In-Depth Information
2.1.1 Structural Features of Meprins
Meprins exhibit unique features among all known astacins; they build the
largest secreted protease known, due to monomer oligomerization yielding
complexes of Mr up to 6 MDa (meprin a) and the only membrane-bound
member (meprin b) (Figure 2.2).
19-22
Meprins are highly glycosylated multi-domain enzymes and, to date,
have been identified only in vertebrates (fish, platypus, rodents, and
humans).
19,20,23-27
Human meprin a and b are encoded on chromosomes 6 and 8, respectively.
28
The proteases are translated with an amino-terminal signal peptide directing
the protein chain to the endoplasmic reticulum, an amino-terminal propeptide,
an astacin-like protease domain, a MAM (meprin A5 protein tyrosine phos-
phatase m) and a TRAF domain (tumour necrosis factor receptor associated
factor), which are known to mediate protein-protein interactions, followed by
an EGF-like (epidermal growth factor-like) module, the C-terminal trans-
membrane domain, and a cytosolic tail.
29
Meprin a, but not meprin b, contains
an additional inserted domain (I-domain), which is proteolytically cleaved in
the secretory pathway, resulting in the loss of the EGF-like, the transmem-
brane, and cytosolic domain and secretion into the extracellular space.
17
While
meprin b is integrated into the plasma membrane as a type I integral protein, in
human cells it may also be shed.
21,30
Both meprins form homo-oligomers,
which can reach the size of several megadaltons in the case of meprin a, whereas
meprin b only forms dimers (Figure 2.2).
19,20
The rodent enzymes, when
coexpressed, can also be organized as heterodimers and predominantly
heterotetramers.
20
2.1.2 Activation of Meprins
Proteases of the astacin family are synthesized as zymogens and thus need to be
activated by cleaving off the propeptides in order to gain full proteolytic
activity.
31-34
In the case of meprins, this activation process has been assigned to
serine proteases such as trypsin, whereas many other astacins, such as BMP-1,
are activated by the proprotein convertase furin.
19,35-37
Outside the intestinal
tract, in the absence of pancreatic trypsin, promeprin a, but not b, can be
activated by plasmin, as shown in colorectal cancer cells.
19,35
Additionally,
neutrophil elastase (NE) was demonstrated to be a potent activator for meprin
a in bronchial epithelial cells.
38
In skin, we have identified human tissue kal-
likrein-related peptidase 4 (klk4), klk5, and klk8 as activators for meprins,
whereas meprin a is activated only by klk 5.
34,39
2.1.3 Substrate and Cleavage Specificity of Meprin a and b
A number of different proteins and biologically active peptides are cleaved by
meprins in vitro, but only a few are known in vivo.
17,38,40,41
Based on these
proteolytic events, it has emerged that meprin b prefers acidic amino acid
