Skeletal dysplasia and lethality in mice lacking the mid-region, nuclear localization signal and C-terminus of parathyroid hormone-related protein

Bone ◽  
2009 ◽  
Vol 44 ◽  
pp. S53
Author(s):  
R.E. Toribio ◽  
H.A. Brown ◽  
C.M. Novince ◽  
L.G. Lanigan ◽  
J.L. Werbeck ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Nuclear Localization ◽  
Skeletal Dysplasia ◽  
Nuclear Localization Signal ◽  
Related Protein ◽  
Parathyroid Hormone Related Protein ◽  
C Terminus ◽  
Localization Signal

scholarly journals Dual role of the adenovirus pVI C terminus as a nuclear localization signal and activator of the viral protease

2004 ◽  
Vol 85 (11) ◽  
pp. 3367-3376 ◽  
Author(s):  
K. S. Honkavuori ◽  
B. D. Pollard ◽  
M. S. Rodriguez ◽  
R. T. Hay ◽  
G. D. Kemp
Keyword(s):  
Nuclear Localization ◽  
Nuclear Localization Signal ◽  
Human Adenovirus ◽  
Dual Role ◽  
Adenovirus Infection ◽  
Heterologous Proteins ◽  
Viral Protease ◽  
C Terminus ◽  
Localization Signal

Adenain, the protease produced by adenovirus, is regulated by formation of a heterodimer with an 11 aa peptide derived from the C terminus of another adenoviral protein, pVI. Here, the role of the basic motif KRRR, which is conserved in pVI sequences from human adenovirus serotypes, was investigated. It was shown that this motif is less important than the N- or C-terminal regions in the formation of the adenain–peptide heterodimer and in the activity of the subsequent complex. This motif, however, acted as a nuclear localization signal that was capable of targeting heterologous proteins to the nucleus, resulting in a distinctive intranuclear distribution consisting of discrete foci, which is similar to that found for pVI during adenovirus infection.

scholarly journals Interaction of the Influenza A Virus Polymerase PB2 C-terminal Region with Importin α Isoforms Provides Insights into Host Adaptation and Polymerase Assembly

2011 ◽  
Vol 286 (12) ◽  
pp. 10439-10448 ◽  
Author(s):  
Stephane Boivin ◽  
Darren J. Hart
Keyword(s):  
Nuclear Localization ◽  
Nuclear Localization Signal ◽  
Influenza A ◽  
Host Adaptation ◽  
New Host ◽  
Adaptive Mutations ◽  
C Terminus ◽  
Importin Α ◽  
Localization Signal ◽  
Import Receptors

In the adaptation of avian viruses to mammalian hosts, mutations in the viral polymerase, notably in the PB2 subunit, play an important role. A PB2 C-terminal domain rich in putative host adaptation residues has been shown to bind importin α nuclear import receptors. Adaptation has been proposed to involve binding of PB2 to importins of the new host. To date PB2-importin complexes have been characterized semiquantitatively with no precise measurement of binding parameters. To investigate the effects of adaptive mutations on importin interaction and selectivity, surface plasmon resonance was used to compare the binding rate constants and affinities of avian H5N1 and human H3N2 PB2 C-terminal variants with importin isoforms human α 1, 3, 5 and 7, and avian α 1. Using purified proteins eliminates host environment effects and permits measurement of intrinsic affinities and rates of complex formation and dissociation. Two effects were observed: first, adaptive mutations D701N, R702K, and S714R in the nuclear localization signal domain increased 2–4-fold the association rates with avian and human importins; second, measurement of different structural forms of the PB2 C terminus demonstrated that the upstream 627 domain reduced binding affinity, consistent with a steric clash predicted from crystal structures. From these kinetic data, structural analyses, and the data of others, a model is proposed in which an increase in charged surface residues during host adaptation increases the association rate of PB2 to cytoplasmic importins and where the C-terminal 627-nuclear localization signal domain may reorganize upon importin binding, consistent with a role in active polymerase assembly.

scholarly journals Phosphorylation at the Cyclin-dependent Kinases Site (Thr85) of Parathyroid Hormone-related Protein Negatively Regulates Its Nuclear Localization

1999 ◽  
Vol 274 (26) ◽  
pp. 18559-18566 ◽  
Author(s):  
Mark H. C. Lam ◽  
Colin M. House ◽  
Tony Tiganis ◽  
Ken I. Mitchelhill ◽  
Boris Sarcevic ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Nuclear Localization ◽  
Related Protein ◽  
Cyclin Dependent Kinases ◽  
Parathyroid Hormone Related Protein

scholarly journals Functional Evolution of the Photolyase/Cryptochrome Protein Family: Importance of the C Terminus of Mammalian CRY1 for Circadian Core Oscillator Performance

2006 ◽  
Vol 26 (5) ◽  
pp. 1743-1753 ◽  
Author(s):  
Inês Chaves ◽  
Kazuhiro Yagita ◽  
Sander Barnhoorn ◽  
Hitoshi Okamura ◽  
Gijsbertus T. J. van der Horst ◽  
...  
Keyword(s):  
Nuclear Localization ◽  
Nuclear Localization Signal ◽  
Coiled Coil ◽  
Structural Similarity ◽  
Light Signaling ◽  
Core Domain ◽  
Coiled Coil Domain ◽  
C Terminus ◽  
Localization Signal ◽  
Species Specific

ABSTRACT Cryptochromes (CRYs) are composed of a core domain with structural similarity to photolyase and a distinguishing C-terminal extension. While plant and fly CRYs act as circadian photoreceptors, using the C terminus for light signaling, mammalian CRY1 and CRY2 are integral components of the circadian oscillator. However, the function of their C terminus remains to be resolved. Here, we show that the C-terminal extension of mCRY1 harbors a nuclear localization signal and a putative coiled-coil domain that drive nuclear localization via two independent mechanisms and shift the equilibrium of shuttling mammalian CRY1 (mCRY1)/mammalian PER2 (mPER2) complexes towards the nucleus. Importantly, deletion of the complete C terminus prevents mCRY1 from repressing CLOCK/BMAL1-mediated transcription, whereas a plant photolyase gains this key clock function upon fusion to the last 100 amino acids of the mCRY1 core and its C terminus. Thus, the acquirement of different (species-specific) C termini during evolution not only functionally separated cryptochromes from photolyase but also caused diversity within the cryptochrome family.

scholarly journals The C-Terminal Region of PTHrP, in Addition to the Nuclear Localization Signal, Is Essential for the Intracrine Stimulation of Proliferation in Vascular Smooth Muscle Cells

Endocrinology ◽  
2001 ◽  
Vol 142 (9) ◽  
pp. 4096-4105 ◽  
Author(s):  
F. de Miguel ◽  
N. Fiaschi-Taesch ◽  
J. C. López-Talavera ◽  
K. K. Takane ◽  
T. Massfelder ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Nuclear Localization ◽  
Nuclear Localization Signal ◽  
Muscle Cells ◽  
Nuclear Entry ◽  
C Terminus ◽  
Localization Signal

Abstract PTHrP is secreted by most cell types. In addition to a paracrine/autocrine role, PTHrP has “intracrine” actions, entering the nuclear compartment under the direction of a classic bipartite nuclear localization signal. In vascular smooth muscle cells, nuclear entry stimulates mitogenesis. In the current study, we sought to more precisely define the regions of PTHrP required for the activation of mitogenesis in vascular smooth muscle cells. PTHrP deletion mutants missing large regions [i.e. the signal peptide, N terminus (1–36), mid region (38–86), nuclear localization signal, C terminus (108–139), or combinations of the above] were expressed in A-10 vascular smooth muscle cells. The consequences on nuclear localization and proliferation were examined. Deletion of the nuclear localization signal prevented nuclear entry and slowed proliferation. Deletion of the highly conserved N terminus or mid region had no impact on nuclear localization or on proliferation. Deletion of the C terminus had no deleterious effect on nuclear localization but dramatically reduced proliferation. Thus, the nuclear localization signal is both necessary and sufficient for nuclear localization of PTHrP. In contrast, activation of proliferation in vascular smooth muscle cells requires both an intact nuclear localization signal and an intact C terminus. Whereas the nuclear localization signal is required for nuclear entry, the C terminus may serve a trans-activating function to stimulate mitogenesis once inside the nucleus of vascular smooth muscle cells.

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