Processing of the lipocalin alpha(1)-microglobulin by hemoglobin induces heme-binding and heme-degradation properties

Blood. 2002 Mar 15;99(6):1894-901. doi: 10.1182/blood.v99.6.1894.

Abstract

Alpha(1)-microglobulin is a 26-kd protein, widespread in plasma and tissues and well-conserved among vertebrates. Alpha(1)-microglobulin belongs to the lipocalins, a protein superfamily with highly conserved 3-dimensional structures, forming an internal ligand binding pocket. The protein, isolated from urine, has a heterogeneous yellow-brown chromophore bound covalently to amino acid side groups around the entrance of the lipocalin pocket. Alpha(1)-microglobulin is found in blood both in free form and complex-bound to immunoglobulin A (IgA) via a half-cystine residue at position 34. It is shown here that an alpha(1)-microglobulin species, which we name t-alpha(1)-microglobulin (t = truncated), with a free Cys34 thiol group, lacking its C-terminal tetrapeptide, LIPR, and with a more polar environment around the entrance of the lipocalin pocket, is released from IgA-alpha(1)-microglobulin as well as from free alpha(1)-microglobulin when exposed to the cytosolic side of erythrocyte membranes or to purified oxyhemoglobin. The processed t-alpha(1)-microglobulin binds heme and the alpha(1)-microglobulin-heme complex shows a time-dependent spectral rearrangement, suggestive of degradation of heme concomitantly with formation of a heterogeneous chromophore associated with the protein. The processed t-alpha(1)-microglobulin is found in normal and pathologic human urine, indicating that the cleavage process occurs in vivo. The results suggest that alpha(1)-microglobulin is involved in extracellular heme catabolism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alpha-Globulins / chemistry
  • Alpha-Globulins / metabolism*
  • Alpha-Globulins / physiology
  • Disulfides / metabolism
  • Erythrocyte Membrane / metabolism
  • Heme / metabolism*
  • Hemoglobins / metabolism*
  • Hemoglobins / physiology
  • Humans
  • Immunoglobulin A / metabolism
  • Kinetics
  • Pepsin A / metabolism
  • Protein Binding
  • Protein Processing, Post-Translational*
  • Radioactive Tracers

Substances

  • Alpha-Globulins
  • Disulfides
  • Hemoglobins
  • Immunoglobulin A
  • Radioactive Tracers
  • alpha-1-microglobulin
  • Heme
  • Pepsin A