Importance of the N terminus of rous sarcoma virus protease for structure and enzymatic function.

All retrovirus proteases (PRs) are homodimers, and dimerization is essential for enzymatic function. The dimer is held together largely by a short four-stranded antiparallel beta sheet composed of the four or five N-terminal amino acid residues and a similar stretch of residues from the C terminus. We have found that the enzymatic and structural properties of Rous sarcoma virus (RSV) PR are exquisitely sensitive to mutations at the N terminus. Deletion of one or three residues, addition of one residue, or substitution of alanine for the N-terminal leucine reduced enzymatic activity on peptide and protein substrates 100- to 1,000-fold. The purified mutant proteins remained monomeric up to a concentration of about 2 mg/ml, as determined by dynamic light scattering. At higher concentrations, dimerization was observed, but the dimer lacked or was deficient in enzymatic activity and thus was inferred to be structurally distinct from a wild-type dimer. The mutant protein lacking three N-terminal residues (DeltaLAM), a form of PR occurring naturally in virions, was examined by nuclear magnetic resonance spectroscopy and found to be folded at concentrations where it was monomeric. This result stands in contrast to the report that a similarly engineered monomeric PR of human immunodeficiency virus type 1 is unstructured. Heteronuclear single quantum coherence spectra of the mutant at concentrations where either monomers or dimers prevail were nearly identical. However, these spectra differed from that of the dimeric wild-type RSV PR. These results imply that the chemical environment of many of the amide protons differed and thus that the three-dimensional structure of the DeltaLAM PR mutant is different from that of the wild-type PR. The structure of this mutant protein may serve as a model for the structure of the PR domain of the Gag polyprotein and may thus give clues to the initiation of proteolytic maturation in retroviruses.

Rehabilitation management of chronic pain syndromes.

Chronic pain is an often misdiagnosed and poorly understood problem. Pain complaints are the most frequently reported symptom to physicians and nurse practitioners. Unremitting pain can have an adverse effect physically, psychologically, and socially. When chronic pain is not relieved, anger, frustration, and depression can lead to maladaptive behaviors that interfere with the person's ability to pursue goals and activities. Chronic pain is best treated through a multidisciplinary approach, with best results achieved by programs specialized in pain management. The goal of rehabilitation in chronic pain management is not total pain relief because this is often impossible; restoration of the ability to function productively and satisfyingly is the target goal.