2Z9T

Crystal structure of the human beta-2 microglobulin mutant W60G

Summary for 2Z9T

• Entry DOI: 10.2210/pdb2z9t/pdb
• Descriptor: Beta-2-microglobulin (2 entities in total)
• Functional Keywords: beta-2-microglobulin, tryptophan, glycine, amyloidosis, dra, beta fibrils, disease mutation, glycation, glycoprotein, immune response, immunoglobulin domain, mhc i, pyrrolidone carboxylic acid, secreted, immune system
• Biological source: Homo sapiens (human)
• Cellular location: Secreted: P61769
• Total number of polymer chains: 1
• Total formula weight: 11750.20

Authors

Ricagno, S.,Bolognesi, M.,Bellotti, V.,Corazza, A.,Rennella, E.,Gural, D.,Mimmi, M.C.,Betto, E.,Pucillo, C.,Fogolari, F.,Viglino, P.,Raimondi, S.,Giorgetti, S.,Bolognesi, B.,Merlini, G.,Stoppini, M. (deposition date: 2007-09-26, release date: 2008-04-22, Last modification date: 2024-11-13)

Primary citation

Esposito, G.,Ricagno, S.,Corazza, A.,Rennella, E.,Gumral, D.,Mimmi, M.C.,Betto, E.,Pucillo, C.E.M.,Fogolari, F.,Viglino, P.,Raimondi, S.,Giorgetti, S.,Bolognesi, B.,Merlini, G.,Stoppini, M.,Bolognesi, M.,Bellotti, V.
The controlling roles of Trp60 and Trp95 in beta2-microglobulin function, folding and amyloid aggregation properties
J.Mol.Biol., 378:885-895, 2008

PubMed Abstract: Amyloidosis associated to hemodialysis is caused by persistently high beta(2)-microglobulin (beta(2)m) serum levels. beta(2)m is an intrinsically amyloidogenic protein whose capacity to assemble into amyloid fibrils in vitro and in vivo is concentration dependent; no beta(2)m genetic variant is known in the human population. We investigated the roles of two evolutionary conserved Trp residues in relation to beta(2)m structure, function and folding/misfolding by means of a combined biophysical and functional approach. We show that Trp60 plays a functional role in promoting the association of beta(2)m in class I major histocompatibility complex; it is exposed to the solvent at the apex of a protein loop in order to accomplish such function. The Trp60-->Gly mutation has a threefold effect: it stabilizes beta(2)m, inhibits beta(2)m amyloidogenic propensity and weakens the interaction with the class I major histocompatibility complex heavy chain. On the contrary, Trp95 is buried in the beta(2)m core; the Trp95-->Gly mutation destabilizes the protein, which is unfolded in solution, yielding nonfibrillar beta(2)m aggregates. Trp60 and Trp95 therefore play differential and complementary roles in beta(2)m, being relevant for function (Trp60) and for maintenance of a properly folded structure (Trp95) while affecting in distinct ways the intrinsic propensity of wild-type beta(2)m towards self-aggregation into amyloid fibrils.

PubMed: 18395224
DOI: 10.1016/j.jmb.2008.03.002

Experimental method

X-RAY DIFFRACTION (1.8 Å)