skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Tertiary structure of human {Lambda}6 light chains.

Abstract

AL amyloidosis is a disease process characterized by the pathologic deposition 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 lambda gene families have been identified in AL deposits, one particular subgroup--lambda 6--has been found to be preferentially associated with this disease. Notably, the variable region of lambda 6 proteins (V lambda 6) has distinctive primary structural features including the presence in the third framework region (FR3) of two additional amino acid residues that distinguish members of this subgroup from other types of light chains. However, the structural consequences of these alterations have not been elucidated. To determine if lambda 6 proteins possess unique tertiary structural features, as compared to light chains of other V lambda subgroups, we have obtained 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-derived plasma cells from a patient (Wil) who had documented AL amyloidosis and another (Jto) with multiple myeloma and tubular cast nephropathy, but nomore » evident fibrillar deposits. The x-ray crystallographic analyses revealed that the two-residue insertion located between positions 68 and 69 (not between 66 and 67 as previously surmised) extended an existing loop region that effectively increased the surface area adjacent to the first complementarity determining 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, as evidenced by the presence in the latter of certain ionic and hydrophobic interactions that we posit increased protein stability and thus prevented amyloid formation.« less

Authors:
; ; ; ; ; ;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE Office of Science (SC); OGA
OSTI Identifier:
942473
Report Number(s):
ANL/CMB/JA-31825
Journal ID: ISSN 1350-6129; TRN: US200916%%546
DOE Contract Number:  
DE-AC02-06CH11357
Resource Type:
Journal Article
Journal Name:
Amyloid : Int. J. Exp. Clin. Invest.
Additional Journal Information:
Journal Volume: 6; Journal Issue: 1999; Journal ID: ISSN 1350-6129
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; AMINO ACIDS; HEMIC DISEASES; HUMAN POPULATIONS; PLASMA CELLS; SURFACE AREA; VISIBLE RADIATION; X-RAY DIFFRACTION

Citation Formats

Pokkuluri, P. R., Solomon, A., Weiss, D. T., Stevens, F. J., Schiffer, M., Center for Mechanistic Biology and Biotechnology, and Univ. of Tennessee Medical Center /Graduate School of Medicine. Tertiary structure of human {Lambda}6 light chains.. United States: N. p., 1999. Web. doi:10.3109/13506129909007322.
Pokkuluri, P. R., Solomon, A., Weiss, D. T., Stevens, F. J., Schiffer, M., Center for Mechanistic Biology and Biotechnology, & Univ. of Tennessee Medical Center /Graduate School of Medicine. Tertiary structure of human {Lambda}6 light chains.. United States. doi:10.3109/13506129909007322.
Pokkuluri, P. R., Solomon, A., Weiss, D. T., Stevens, F. J., Schiffer, M., Center for Mechanistic Biology and Biotechnology, and Univ. of Tennessee Medical Center /Graduate School of Medicine. Fri . "Tertiary structure of human {Lambda}6 light chains.". United States. doi:10.3109/13506129909007322.
@article{osti_942473,
title = {Tertiary structure of human {Lambda}6 light chains.},
author = {Pokkuluri, P. R. and Solomon, A. and Weiss, D. T. and Stevens, F. J. and Schiffer, M. and Center for Mechanistic Biology and Biotechnology and Univ. of Tennessee Medical Center /Graduate School of Medicine},
abstractNote = {AL amyloidosis is a disease process characterized by the pathologic deposition 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 lambda gene families have been identified in AL deposits, one particular subgroup--lambda 6--has been found to be preferentially associated with this disease. Notably, the variable region of lambda 6 proteins (V lambda 6) has distinctive primary structural features including the presence in the third framework region (FR3) of two additional amino acid residues that distinguish members of this subgroup from other types of light chains. However, the structural consequences of these alterations have not been elucidated. To determine if lambda 6 proteins possess unique tertiary structural features, as compared to light chains of other V lambda subgroups, we have obtained 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-derived plasma cells from a patient (Wil) who had documented AL amyloidosis and another (Jto) with multiple myeloma and tubular cast nephropathy, but no evident fibrillar deposits. The x-ray crystallographic analyses revealed that the two-residue insertion located between positions 68 and 69 (not between 66 and 67 as previously surmised) extended an existing loop region that effectively increased the surface area adjacent to the first complementarity determining 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, as evidenced by the presence in the latter of certain ionic and hydrophobic interactions that we posit increased protein stability and thus prevented amyloid formation.},
doi = {10.3109/13506129909007322},
journal = {Amyloid : Int. J. Exp. Clin. Invest.},
issn = {1350-6129},
number = 1999,
volume = 6,
place = {United States},
year = {1999},
month = {1}
}