Tertiary structure of human lambda 6 light chains

AL amyloidosis is a disease process characterized by the pathologic deposit ion of monoclonal light chains in tissue. To date, only limited information has been obtained on the molecular features that render such light chains amyloidogenic. Although protein products of the major human V-kappa and V-l ambda gene families have been identified in AL deposits, one particular sub group - lambda 6 - has been found to be preferentially associated with this disease. Notably, the variable region of lambda 6 proteins (V(lambda)6) ha s distinctive primary structural features including the presence in the thi rd framework region (FR3) of two additional amino acid residues that distin guish members of this subgroup from other types of light chains. However, t he structural consequences of these alterations have not been elucidated. T o determine if lambda 6 proteins possess unique tertiary structural feature s, as compared to light chains of other V-lambda subgroups, we have obtaine d x-ray diffraction data on crystals prepared from two recombinant V(lambda )6 molecules. These components, isolated from a bacterial expression system , were generated from lambda 6-related cDNAs cloned from bone marrow-derive d plasma cells from a patient (Wil) who had documented AL amyloidosis and a nother (Jto) with multiple myeloma and tubular cast nephropathy, but no evi dent fibrillar deposits. The xray crystallographic analyses revealed that t he two-residue insertion located between positions 68 and 69 (not between 6 6 and 67 as previously surmised) extended an existing loop region that effe ctively increased the surface area adjacent to the first complementarity de termining region (CDR1). Further, an unusual interaction between the Arg 25 and Phe 2 residues commonly found in lambda 6 molecules was noted. However , the structures of V(lambda)6 Wil and Jto also differed from each other, a s evidenced by the presence in the latter of certain ionic and hydrophobic interactions that we posit increased protein stability and thus prevented a myloid formation.