Classification of mononuclear zinc metal sites in protein structures

Our study of the extended metal environment, particularly of the second shell, focuses in this paper on zinc sites. Key findings include: (i) The second shell of mononuclear zinc centers is generally more polar than hydrophobic and prominently features charged residues engaged in an abundance of hydrogen bonding with histidine ligands. Histidine–acidic or histidine–tyrosine clusters commonly overlap the environment of zinc ions. (ii) Histidine tautomeric metal bonding patterns in ligating zinc ions are mixed. For example, carboxypeptidase A, thermolysin, and sonic hedgehog possess the same ligand group (two histidines, one unibidentate acidic ligand, and a bound water), but their histidine tautomeric geometries markedly differ such that the carboxypeptidase A makes only Nδ1 contacts, thermolysin makes only Nɛ2 contacts, and sonic hedgehog uses one of each. Thus the presence of a similar ligand cohort does not necessarily imply the same topology or function at the active site. (iii) Two close histidine ligands HXmH, m ≤ 5, rarely both coordinate a single metal ion in the Nδ1 tautomeric conformation, presumably to avoid steric conflicts. Mononuclear zinc sites can be classified into six types depending on the ligand composition and geometry. Implications of the results are discussed in terms of divergent and convergent evolution.

The corticofugal system for hearing: Recent progress

Peripheral auditory neurons are tuned to single frequencies of sound. In the central auditory system, excitatory (or facilitatory) and inhibitory neural interactions take place at multiple levels and produce neurons with sharp level-tolerant frequency-tuning curves, neurons tuned to parameters other than frequency, cochleotopic (frequency) maps, which are different from the peripheral cochleotopic map, and computational maps. The mechanisms to create the response properties of these neurons have been considered to be solely caused by divergent and convergent projections of neurons in the ascending auditory system. The recent research on the corticofugal (descending) auditory system, however, indicates that the corticofugal system adjusts and improves auditory signal processing by modulating neural responses and maps. The corticofugal function consists of at least the following subfunctions. (i) Egocentric selection for short-term modulation of auditory signal processing according to auditory experience. Egocentric selection, based on focused positive feedback associated with widespread lateral inhibition, is mediated by the cortical neural net working together with the corticofugal system. (ii) Reorganization for long-term modulation of the processing of behaviorally relevant auditory signals. Reorganization is based on egocentric selection working together with nonauditory systems. (iii) Gain control based on overall excitatory, facilitatory, or inhibitory corticofugal modulation. Egocentric selection can be viewed as selective gain control. (iv) Shaping (or even creation) of response properties of neurons. Filter properties of neurons in the frequency, amplitude, time, and spatial domains can be sharpened by the corticofugal system. Sharpening of tuning is one of the functions of egocentric selection.

Convergent evolution of apolipoprotein(a) in primates and hedgehog

Apolipoprotein(a) [apo(a)] is the distinguishing protein component of lipoprotein(a), a major inherited risk factor for atherosclerosis. Human apo(a) is homologous to plasminogen. It contains from 15 to 50 repeated domains closely related to plasminogen kringle four, plus single kringle five-like and inactive protease-like domains. This expressed gene is confined to a subset of primates. Although most mammals lack apo(a), hedgehogs produce an apo(a)-like protein composed of highly repeated copies of a plasminogen kringle three-like domain, with complete absence of protease domain sequences. Both human and hedgehog apo(a)-like proteins form covalently linked lipoprotein particles that can bind to fibrin and other substrates shared with plasminogen. DNA sequence comparisons and phylogenetic analysis indicate that the human type of apo(a) evolved from a duplicated plasminogen gene during recent primate evolution. In contrast, the kringle three-based type of apo(a) evolved from an independent duplication of the plasminogen gene approximately 80 million years ago. In a type of convergent evolution, the plasminogen gene has been independently remodeled twice during mammalian evolution to produce similar forms of apo(a) in two widely divergent groups of species.