The Structure of Calreticulin C-terminal Domain Is Modulated by Physiological Variations of Calcium Concentration

ANA MARÍA VILLAMIL GIRALDO, MA´XIMO LOPEZ MEDUS, MARIANO GONZALEZ LEBRERO, RODRIGO S. PAGANO, CARLOS A. LABRIOLA, LUCAS LANDOLFO, JOSE´ M. DELFINO, ARMANDO J. PARODI, AND JULIO J. CARAMELO

JOURNAL OF BIOLOGICAL CHEMISTRY (ONLINE)

American Society for Biochemistry and Molecular Biology

Lugar: United States; Año: 2010 vol. 285 p. 4544 - 4553

1083-351X

Calreticulin is an abundant endoplasmic reticulum residentprotein that fulfills at least two basic functions. Firstly, due to itsability to bind monoglucosylated high mannose oligosaccharides,calreticulin is a central component of the folding qualitycontrol system of glycoproteins.Onthe other hand, thanks to itscapacity to bind high amounts of calcium, calreticulin is one ofthe main calcium buffers in the endoplasmic reticulum. This lastactivity resides on a highly negatively charged domain located atthe C terminus. Interestingly, this domain has been proposed toregulate the intracellular localization of calreticulin. Structuralinformation for this domain is currently scarce. Here we addressthis issue by employing a combination of biophysical techniquesand molecular dynamics simulation. We found that calreticulinC-terminal domain at low calcium concentration displays a disorderedstructure, whereas calcium addition induces a more rigidand compact conformation. Remarkably, this change developswhen calcium concentration varies within a range similar to thattaking place in the endoplasmic reticulum upon physiological fluctuations.In addition, a much higher calcium concentration is necessaryto attain similar responses in a peptide displaying a randomizedsequence of calreticulin C-terminal domain, illustrating thesequence specificity of this effect. Molecular dynamics simulationreveals that this ordering effect is a consequence of the ability ofcalcium to bring into close proximity residues that lie apart in theprimary structure. These results place calreticulin in a new settingin which the protein behaves not only as a calcium-binding proteinbut as a finely tuned calcium sensor.