INVESTIGADORES
GONZALEZ LEBRERO Mariano Camilo
artículos
Título:
The structure of calreticulin C-terminal domain is modulated by physiological variations of calcium concentration.
Autor/es:
VILLAMIL GIRALDO AM; LOPEZ MEDUS M; GONZALEZ LEBRERO MC; PAGANO RS; LABRIOLA CA; LANDOLFO L; DELFINO JM; PARODI AJ; CARAMELO JJ
Revista:
JOURNAL OF BIOLOGICAL CHEMISTRY
Editorial:
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Referencias:
Año: 2010 vol. 285 p. 4544 - 4553
ISSN:
0021-9258
Resumen:
Calreticulin is an abundant endoplasmic reticulum resident protein that
fulfills at least two basic functions. Firstly, due to its ability to
bind monoglucosylated high mannose oligosaccharides, calreticulin is a
central component of the folding quality control system of
glycoproteins. On the other hand, thanks to its capacity to bind high
amounts of calcium, calreticulin is one of the main calcium buffers in
the endoplasmic reticulum. This last activity resides on a highly
negatively charged domain located at the C terminus. Interestingly,
this domain has been proposed to regulate the intracellular
localization of calreticulin. Structural information for this domain is
currently scarce. Here we address this issue by employing a combination
of biophysical techniques and molecular dynamics simulation. We found
that calreticulin C-terminal domain at low calcium concentration
displays a disordered structure, whereas calcium addition induces a
more rigid and compact conformation. Remarkably, this change develops
when calcium concentration varies within a range similar to that taking
place in the endoplasmic reticulum upon physiological fluctuations. In
addition, a much higher calcium concentration is necessary to attain
similar responses in a peptide displaying a randomized sequence of
calreticulin C-terminal domain, illustrating the sequence specificity
of this effect. Molecular dynamics simulation reveals that this
ordering effect is a consequence of the ability of calcium to bring
into close proximity residues that lie apart in the primary structure.
These results place calreticulin in a new setting in which the protein
behaves not only as a calcium-binding protein but as a finely tuned
calcium sensor.