Lecture # 16
ADAMs, ADAMTSs and Laminin and epithelial morphogenesis
(embryoid body formation)
Manso et al (2006) Integrins, membrane-type metalloproteinases and ADAMS:
potential implications for cardiac remodeling.
Cardiovascular research 69: 574-584
Primakoff and Myles (2000) The ADAM gene family: surface proteins with
adhesion and protease activity Trends in Genetic 16: 83-87
The structures of ADAMs consist of a prodomain, a metalloproteinase domain, a
disintegrin domain, a metalloproteinase domain,
a disintegrin domain
, a cysteine-rich
domain, a transmembrane domain, and a cytoplasmic tail.
The N-terminal prodomain
functions principally to keep the metalloproteinase site inactive, but also acts as a
chaperone for proper folding of ADAMSs’ metalloproteinase domain.
metalloproteinase domain hydrolyzes protein substrates such as cytokines and growth
The disintegrin domain binds matrix ligands of integrin receptors such as
Eleven ADAM disintegrin domains are known to interact with integrin
receptors at the specific location of the “disintegrin loop” found on many ADAM
ADAMS cleavage schematic shown in class
The ADAMs (white) uses its disintegrin domain to bind to the substrate (dark grey) and
uses it zinc-containing metalloproteinase active site to cleave the substrate.
cleavage, the substrate undergoes conformation change, dissociates from the disintegrin
domain and the substrate’s large extracellular fragment is released from the cell surface.
Another version of the model, the ADAM (white) uses its disintegrin domain to bind to a
substrate-associated protein (light grey) and uses its zinc-containing metalloproteinase
active site to cleave the substrate (dark grey).
Following cleavage, the substrate
undergoes conformational change, dissociates from the substrate-associated-protein and
the substrate’s large extracellular fragment is released from the cell surface.
Some ADAM proteases are sheddases
During development and in the adult, cells have the ability to modify their surface to
regulate various kinds of functions.
For example, the extracellular domain of >40 plasma
membrane-anchored cytokines, growth factors, receptors, adhesion molecules
enzymes can be cleaved and thereby released (shed) from the plasma membrane by
various proteases (called sheddases or secretases).
These sheddases are themselves
transmembrane proteins and, in several cases, are ADAMs and MT-MMPs.
The role of ADAM-12 in the hypertrophic process
GPCR (G-protein coupled receptors) stimulation by agonists such as PE, AII or ET-1 (see
slide) leads to ADAM-12 activation.
The activated ADAM evokes ectodomain shedding