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The tertiary structure and backbone dynamics of human prolactin.
- Source :
-
Journal of molecular biology [J Mol Biol] 2003 May 16; Vol. 328 (5), pp. 1105-21. - Publication Year :
- 2003
-
Abstract
- Human prolactin is a 199-residue (23 kDa) protein closely related to growth hormone and placental lactogen with properties and functions resembling both a hormone and a cytokine. As a traditional hormone, prolactin is produced by lactotrophic cells in the pituitary and secreted into the bloodstream where it acts distally to regulate reproduction and promote lactation. Pituitary cells store prolactin in secretory granules organized around large prolactin aggregates, which are produced within the trans layer of the Golgi complex. Extrapituitary prolactin is synthesized by a wide variety of cells but is not stored in secretory granules. Extrapituitary prolactin displays immunomodulatory activities and acts as a growth factor for cancers of the breast, prostate and tissues of the female reproductive system. We have determined the tertiary structure of human prolactin using three-dimensional (3D) and four-dimensional (4D) heteronuclear NMR spectroscopy. As expected, prolactin adopts an "up-up-down-down" four-helical bundle topology and resembles other members of the family of hematopoietic cytokines. Prolactin displays three discrete structural differences from growth hormone: (1) a structured N-terminal loop in contact with the first helix, (2) a missing mini-helix in the loop between the first and second helices, and (3) a shorter loop between the second and third helices lacking the perpendicular mini-helix observed in growth hormone. Residues necessary for functional binding to the prolactin receptor are clustered on the prolactin surface in a position similar to growth hormone. The backbone dynamics of prolactin were investigated by analysis of 15N NMR relaxation phenomena and demonstrated a rigid four-helical bundle with relatively mobile interconnecting loops. Comparison of global macromolecular tumbling at 0.1mM and 1.0mM prolactin revealed reversible oligomerization, which was correlated to dynamic light scattering experiments. The existence of a reversible oligomerization reaction in solution provides insight into previous results describing the in vitro and in vivo aggregation properties of human prolactin.
- Subjects :
- Amino Acid Sequence
Epitopes chemistry
Female
Human Growth Hormone chemistry
Human Growth Hormone genetics
Humans
Light
Male
Models, Molecular
Molecular Sequence Data
Nuclear Magnetic Resonance, Biomolecular
Prolactin genetics
Protein Structure, Secondary
Protein Structure, Tertiary
Scattering, Radiation
Sequence Homology, Amino Acid
Thermodynamics
Prolactin chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 0022-2836
- Volume :
- 328
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Journal of molecular biology
- Publication Type :
- Academic Journal
- Accession number :
- 12729745
- Full Text :
- https://doi.org/10.1016/s0022-2836(03)00367-x