期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 287, 期 40, 页码 33163-33178出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M112.392258
关键词
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资金
- National Institutes of Health [GM035649, HL047020]
- Robert A. Welch Foundation Grant [C-0612]
- Italian Ministry of University and Scientific Research Grant FIRB Project Biologia Strutturale, [RBLA03B3KC]
- University of Milano
- Fund for Scientific Research Flanders Project Hypoxia and Nerve Globins Grant [G.0331.04N]
Although molecular dynamics simulations suggest multiple interior pathways for O-2 entry into and exit from globins, most experiments indicate well defined single pathways. In 2001, we highlighted the effects of large-to-small amino acid replacements on rates for ligand entry and exit onto the three-dimensional structure of sperm whale myoglobin. The resultant map argued strongly for ligand movement through a short channel from the heme iron to solvent that is gated by the distal histidine (His-64(E7)) near the solvent edge of the porphyrin ring. In this work, we have applied the same mutagenesis mapping strategy to the neuronal mini-hemoglobin from Cerebratulus lacteus (CerHb), which has a large internal tunnel from the heme iron to the C-terminal ends of the E and H helices, a direction that is 180 opposite to the E7 channel. Detailed comparisons of the new CerHb map with expanded results for Mb show unambiguously that the dominant (> 90%) ligand pathway in CerHb is through the internal tunnel, and the major (> 75%) ligand pathway in Mb is through the E7 gate. These results demonstrate that: 1) mutagenesis mapping can identify internal pathways when they exist; 2) molecular dynamics simulations need to be refined to address discrepancies with experimental observations; and 3) alternative pathways have evolved in globins to meet specific physiological demands.
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