Biomedical Engineering Reference
In-Depth Information
4.2.4
Structure and Function of Biomineralization Proteins
Ever since the discovery of the DNA double helix structure by Watson and Crick,
structural biology has made great contributions to progress in the life sciences.
This is because the functions of biopolymers can be inferred from their static
structures. In many cases, protein function mechanisms can be understood by
revealing their tertiary structures. If a protein does not have such a structure, it
is impossible to determine that structure by any means. Many proteins involved
in biomineralization do not have such a stable structure, making it difficult to
determine a static tertiary structure using X-ray crystallography or nuclear magnetic
resonance (NMR) analysis. Proteins that cannot fold into a stable structure are called
“intrinsically disordered proteins” or “natively unfolded proteins” [
23
]. There are
about 20,000 genes in the human genome, and approximately 100,000 proteins
are synthesized from the genes through mechanisms including alternative splicing,
which increase protein diversity. It is suggested that 33% of eukaryotic proteins
contain unfolded regions lacking a stable structure [
24
,
25
]. Proteins with unfolded
regions are considered advantageous for binding multiple targets or for binding
tightly to target compounds [
26
,
27
].
The “lock and key” and the “induced-fit” models were proposed to explain how
proteins recognize their substrates. In the “lock and key” model, the protein already
has a structure complementary to its substrate. In the “induced fit model,” the
protein does not have a complementary structure, but formation of one is induced
by interaction with the substrate. Common to both models is that the protein itself
has a clear stable structure regardless of the experimental conditions, including the
presence or absence of a substrate.
In contrast, it has been suggested that natively unfolded proteins can bind to
substrates through a mechanism called “conformational selection” [
28
]. That is, a
protein has multiple metastable conformations in the absence of a substrate and
fluctuates continuously between the conformations. In the presence of a substrate, a
metastable conformation complementary to the substrate is selected, and a complex
is formed. The selected conformation becomes the most stable conformation. For
example, the ubiquitin polypeptide, consisting of 76 amino acid residues, can form
complexes with many different proteins; a total of 46 crystal structures have been
reported to date. Analysis of the dynamics of ubiquitin in solution by NMR revealed
a group of structures including the 46 crystal structures, thereby validating the
concept of “conformational selection” [
29
].
For proteins involved in biomineralization, one report on statherin is noteworthy.
Statherin is a small 43-amino acid protein found in saliva that inhibits the formation
and growth of HAP crystals. The C-terminus of statherin does not have an ordered
conformation in solution; however, structural analysis using solid-state NMR
indicated that the C-terminal domain forms an
-helix upon binding to HAP [
30
].
The binding of statherin to HAP occurs mainly through charged amino acids at the
N-terminus [
31
,
32
], and the interaction of the C-terminus with HAP is not tight
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