Using NextGen sequencing to identify the molecular basis for genetic disease: an evolutionary perspective

Mitochondria are essential organelles which perform complex and varied functions within eukaryotic cells. Maintenance of mitochondrial health and functionality is thus a key cellular priority and relies on the organelle's extensive proteome. The mitochondrial proteome is largely encoded by nuclear genes, and mitochondrial proteins must be sorted to the correct mitochondrial sub-compartment post-translationally. This essential process is carried out by multimeric and dynamic translocation and sorting machineries, which can be found in all four mitochondrial compartments. Interestingly, advances in the diagnosis of genetic disease have revealed that mutations in various components of the human import machinery can cause mitochondrial disease, a heterogenous and often severe collection of disorders associated with energy generation defects and a multisystem presentation often affecting the cardiovascular and nervous systems. Here, we review our current understanding of mitochondrial protein import systems in human cells and the molecular basis of mitochondrial diseases caused by defects in these pathways.

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Molecular Architecture of the Bardet-Biedl Syndrome Protein 2-7-9 Subcomplex

10.1101/699223 ◽

2019 ◽

Author(s):

W. Grant Ludlam ◽

Takuma Aoba ◽

Jorge Cuéllar ◽

M. Teresa Bueno-Carrasco ◽

Aman Makaju ◽

...

Keyword(s):

Genetic Disease ◽

Molecular Basis ◽

Primary Cilia ◽

Molecular Model ◽

Coiled Coil ◽

Chemical Crosslinking ◽

Molecular Architecture ◽

Bardet Biedl Syndrome ◽

Helical Domain ◽

Syndrome Protein

SummaryBardet-Biedl syndrome (BBS) is a genetic disease caused by mutations that disrupt the function of the BBSome, an eight-subunit complex that plays an important role in transport of proteins in primary cilia. To better understand the molecular basis of the disease, we analyzed the structure of a BBSome subcomplex consisting of three homologous BBS proteins (BBS2, BBS7, and BBS9) by an integrative structural modeling approach using electron microscopy and chemical crosslinking coupled with mass spectrometry. The resulting molecular model revealed an overall structure that resembles a flattened triangle. Within the structure, BBS2 and BBS7 form a tight dimer based on a coiled-coil interaction, and BBS9 associates with the dimer via an interaction with the α-helical domain of BBS2. Interestingly, a BBS-linked mutation of BBS2 (R632P) is located in the α-helical domain at the interface between BBS2 and BBS9, and binding experiments showed that this mutation disrupted the interaction of BBS2 with BBS9. This finding suggests that BBSome assembly is disrupted by the R632P substitution, providing a molecular explanation for BBS in patients harboring this mutation.

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Renilla Bioluminescence: A Morphologic Approach to the Location of Photocytes

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100051050 ◽

1974 ◽

Vol 32 ◽

pp. 208-209

Author(s):

Ben O. Spurlock ◽

Milton J. Cormier

Keyword(s):

Excited State ◽

Ground State ◽

Molecular Basis ◽

Light Emission ◽

Chemical Basis ◽

Electronic Excited State ◽

Colonial Form ◽

The Common ◽

Eighteenth And Nineteenth Centuries ◽

Catalyzed Oxidation

The phenomenon of bioluminescence has fascinated layman and scientist alike for many centuries. During the eighteenth and nineteenth centuries a number of observations were reported on the physiology of bioluminescence in Renilla, the common sea pansy. More recently biochemists have directed their attention to the molecular basis of luminosity in this colonial form. These studies have centered primarily on defining the chemical basis for bioluminescence and its control. It is now established that bioluminescence in Renilla arises due to the luciferase-catalyzed oxidation of luciferin. This results in the creation of a product (oxyluciferin) in an electronic excited state. The transition of oxyluciferin from its excited state to the ground state leads to light emission.

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Androgen-induced plasticity at a “vocal” neuromuscular synapse

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100167895 ◽

1994 ◽

Vol 52 ◽

pp. 32-33

Author(s):

Darcy B. Kelley ◽

Martha L. Tobias ◽

Mark Ellisman

Keyword(s):

Xenopus Laevis ◽

Motor Neurons ◽

Sexual Differentiation ◽

Molecular Basis ◽

Neuromuscular Synapse ◽

Sexually Dimorphic ◽

Intracellular Protein ◽

Developmental Program ◽

Androgen Action ◽

Clawed Frog

Brain and muscle are sexually differentiated tissues in which masculinization is controlled by the secretion of androgens from the testes. Sensitivity to androgen is conferred by the expression of an intracellular protein, the androgen receptor. A central problem of sexual differentiation is thus to understand the cellular and molecular basis of androgen action. We do not understand how hormone occupancy of a receptor translates into an alteration in the developmental program of the target cell. Our studies on sexual differentiation of brain and muscle in Xenopus laevis are designed to explore the molecular basis of androgen induced sexual differentiation by examining how this hormone controls the masculinization of brain and muscle targets.Our approach to this problem has focused on a highly androgen sensitive, sexually dimorphic neuromuscular system: laryngeal muscles and motor neurons of the clawed frog, Xenopus laevis. We have been studying sex differences at a synapse, the laryngeal neuromuscular junction, which mediates sexually dimorphic vocal behavior in Xenopus laevis frogs.

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