CD147, a member of the immunoglobulin superfamily (IgSF),
plays fundamental roles in intercellular interactions in numerous
pathological and physiological processes. Importantly, our
previous studies have demonstrated that HAb18G/CD147 is a
novel hepatocellular carcinoma (HCC)-associated antigen, and
HAb18G/CD147 stimulates adjacent fibroblasts and HCC cells
to produce elevated levels of several matrix metalloproteinases,
facilitating invasion and metastasis of HCC cells. In addition,
HAb18G/CD147 has also been shown to be a novel universal
cancer biomarker for diagnosis and prognostic assessment of a
wide range of cancers. However, the structural basis underlying
the multifunctional character of CD147 remains unresolved.
We report here the crystal structure of the extracellular portion
of HAb18G/CD147 at 2.8A˚ resolution. The structure comprises
an N-terminal IgC2 domain and a C-terminal IgI domain, which
are connected by a 5-residue flexible linker. This unique C2-I
domain organization is distinct from those of other IgSF members.
Four homophilic dimers exist in the crystal and adopt C2-C2
and C2-I dimerization rather than V-V dimerization commonly
found in other IgSF members. This type of homophilic association
thus presents a novel model for homophilic interaction between
C2 domains of IgSF members. Moreover, the crystal structure of
HAb18G/CD147 provides a good structural explanation for the
established multifunction of CD147 mediated by homo/heterooligomerizations
and should represent a general architecture
of other CD147 family members.